How useful is an animal's tail? For the gecko, unlike most animals, it could be a matter of life or death, according to new research from the University of California, Berkeley.
In a paper appearing this week in the online early edition of the journal Proceedings of the National Academy of Sciences, UC Berkeley biologists report that geckos rely on their tails to keep from falling off vertical surfaces and, if they do fall, to right themselves in midair and maneuver like a skydiver gliding to a safe landing.
The discovery is already helping engineers design better climbing robots and may aid in the design of unmanned gliding vehicles or spacecraft. Perhaps, the researchers say, an "active" tail could help astronauts maneuver in space.
According to senior author Robert J. Full, professor of integrative biology at UC Berkeley, previous experiments on geckos have focused on their unique toes as the key to running up a wall and hanging onto ceilings. Full discovered six years ago that, while claws help geckos climb rough surfaces, millions of microscopic toe hairs make it possible for them to climb smooth ones.
Only when engineers began building gecko-like robots, such as Boston Dynamics Inc.'s RiSE (Robot in Scansorial Environment), the University of Pennsylvania's DynaClimber and Stanford University robots Spinybot and Stickybot - all inspired by Full's findings - did they discover that a tail might be necessary to prevent the robot from pitching backward and falling when it slips on a vertical surface.
When Full and UC Berkeley graduate student Ardian Jusufi went back to the lab to look at how geckos, specifically the flat-tailed house gecko, Cosymbotus platyurus, of Southeast Asia, use their tails, they discovered that the tail is critical for dealing with slippery surfaces.
"When we ran all of our geckos on perfect surfaces, they never slipped, and they didn't use their tails," Full said. "But when we put in a slippery patch, we found that they have an active tail that functions like a fifth leg to keep them from tipping backward. This is an undiscovered function for tails that tells us a lot about how active tails could affect the performance of vertebrates."
With the help of high-speed video, the researchers discovered that when a gecko loses traction with one leg, it taps its tail on the surface to prevent pitch-back until the toes can grab hold again. This all happens in milliseconds, since geckos can run up a wall at speeds of 3 feet per second, stepping and peeling off their toes 30 times per second.
If a gecko loses traction with more than one foot, the researchers found, it will often flatten its tail to the surface to prevent a fall in a move that has the effect, says Full, of a bicycle kickstand. Using either the tail-tapping or tail-flattening technique, nearly all geckos were able to navigate across slippery patches on a vertical wall.
"We were really surprised to see that they could pitch back up to 60 degrees, return to the vertical surface and still traverse the slippery patches," Jusufi said.
The engineers with whom Full collaborates are now devising active tails for their robots to replicate these moves, which in a gecko are probably reflexive, Full said.
The researchers acknowledged the usefulness of tails in other animals: kangaroos lean on theirs; chameleons, lemurs and New World monkeys grasp with theirs; and dinosaurs may have used theirs for balance while running and walking. Unlike these more static uses, however, the gecko's tail actively helps in high-speed vertical climbing and gliding.
During the slippery wall experiments, Jusufi and Full noticed something else about the geckos when they fell. They nearly always made a four-point landing after using their tails to reorient themselves in mid-air. Using high-speed video to record geckos falling upside down from a fake leaf, they found that the geckos rotated their tails so that their bodies counter-rotated to face downward, then spread their legs and toes to parachute. This mid-air maneuver was possible because of the gecko's typically large tail, which can be filled with fat.
While this parachuting had been noticed before by other researchers, the role of the tail was first recognized by Full and Jusufi.
"Air righting in mammals is characterized by a bending and twisting of the spine," Jusufi said. Cats, whose mid-air twists have been particularly well studied since 1894, are able to land on four paws with or without a tail. In contrast, he said, "the gecko is keeping its limbs and spine absolutely immobile in nearly 70 percent of all trials, and only rotates its tail until it turns around."
Moreover, after turning face down, the geckos in the study often used their tails to maneuver in mid-air like a skydiver steering toward a targeted drop zone. In wind tunnel tests, geckos could actually hover in the air stream and, using their tails, steer toward a solid perch.
"Why go into this Superman posture?" Full asked. "We found that it allowed them to use their tails to turn or control yaw and pitch. In the wild, this might allow a gecko escaping a predator to just go off the end of a branch and maneuver to another place."
Pitch refers to a head-down versus tail-down position, while yaw is a rotation to the left or right around a vertical axis.
Jusufi is now observing geckos in the wild to determine how these aerobatic skills serve them in the forest.
"We believe these animals are using their tails instead of their bodies to simplify control," he said. "Geckos reorient mainly around one axis, whereas air-righting maneuvers in mammals involve several axes and appear to require far more coordination."
"This discovery is another example of how basic research leads to unexpected applications - new climbing and gliding robots, highly maneuverable unmanned aerial vehicles and even energy-efficient control in space vehicles," said Full, who directs UC Berkeley's new Center for Interdisciplinary Bio-inspiration in Education and Research (CiBER). CiBER's goal is to discover principles that will inspire engineers from academia and industry to develop new materials and design novel robots, but also to seek feedback from engineering successes and failures to suggest new biological hypotheses.
Jusufi and Full are continuing their study of how the gecko uses its tail, and they plan to look at other lizards to determine how widespread this behavior is.
Coauthors with Jusufi and Full are former UC Berkeley postdoctoral fellow Daniel Goldman, now a professor at the Georgia Institute of Technology, and UC Berkeley graduate student Shai Revzen.
The research was supported by grants from the Defense Advanced Research Projects Agency, the National Science Foundation, the Kurt and Barbara Gilgen Fund and The Burroughs Wellcome Fund.
Source: Robert Sanders
University of California - Berkeley
вторник, 7 июня 2011 г.
понедельник, 6 июня 2011 г.
Preventing Metastasis To 'Stop Cancer From Killing People'
Metastasis is the ability of cancer cells to spread from a primary site, to form tumours at distant sites. It is a complex process in which cell motility and invasion play a fundamental role. Essential to our understanding of how metastasis develops is identification of the molecules, and characterisation of the mechanisms that regulate cell motility. Hitherto, these mechanisms have been poorly understood. Now, a team of researchers lead by Professor Marco Falasca at Barts and The London School of Medicine and Dentistry has shown not only that the enzyme phospholipase CОі1 (PLCОі1) plays a crucial role in metastasis formation, but that down regulation of PLCОі1 expression is able to revert metastasis progression.
The team investigated the role of PLCОі1 in cell invasion and metastasis using different approaches to modulate its expression in highly invasive cancer cell lines. Their results showed that PLCОі1 is required for breast cancer cell invasion and activation of the protein Rac1. They revealed a functional link between PLCОі1 and Rac1 that provides insight into processes regulating cell invasion.
Professor Falasca explained: "Consistent with these data we detected an increase in PLC1 expression in metastases compared to primary tumours in breast cancer patients. Therefore PLCОі1 is critical for metastasis formation, and development and inhibition of this enzyme has a therapeutic potential in the treatment of metastasis dissemination."
"This is an exciting discovery. He has shown that turning off this molecule prevents metastasis. The simple fact is that if you stop metastasis, you stop cancer from killing people. We now need to focus on developing drugs that can block PLCОі1."
'Phospholipase CОі1 is Required for Metastasis Development and Progression' is published in Cancer Research.
The research was supported by The Association for International Cancer Research and by the European Commission FP6 program Apotherapy.
Notes:
Barts and The London School of Medicine and Dentistry
Barts and The London School of Medicine and Dentistry - at Queen Mary, University of London - offers international levels of excellence in research and teaching while serving a population of unrivalled diversity amongst which cases of diabetes, hypertension, heart disease, TB, oral disease and cancers are prevalent, within east London and the wider Thames Gateway. Through partnership with our linked trusts, notably Barts and The London NHS Trust, and our associated University Hospital trusts - Homerton, Newham, Whipps Cross and Queen's - the School's research and teaching is informed by an exceptionally wide ranging and stimulating clinical environment.
At the heart of the School's mission lies world class research, the result of a focused programme of recruitment of leading research groups from the UK and abroad and a ВЈ100 million investment in state-of-the-art facilities. Research is focused on translational research, cancer, cardiology, clinical pharmacology, inflammation, infectious diseases, stem cells, dermatology, gastroenterology, haematology, diabetes, neuroscience, surgery and dentistry.
The School is nationally and internationally recognised for research in these areas, reflected in the ВЈ40 million it attracts annually in research income. Its fundamental mission, with its partner NHS Trusts, and other partner organisations such as CRUK, is to ensure that that the best possible clinical service is underpinned by the very latest developments in scientific and clinical teaching, training and research.
Source: Alex Fernandes
Queen Mary, University of London
The team investigated the role of PLCОі1 in cell invasion and metastasis using different approaches to modulate its expression in highly invasive cancer cell lines. Their results showed that PLCОі1 is required for breast cancer cell invasion and activation of the protein Rac1. They revealed a functional link between PLCОі1 and Rac1 that provides insight into processes regulating cell invasion.
Professor Falasca explained: "Consistent with these data we detected an increase in PLC1 expression in metastases compared to primary tumours in breast cancer patients. Therefore PLCОі1 is critical for metastasis formation, and development and inhibition of this enzyme has a therapeutic potential in the treatment of metastasis dissemination."
"This is an exciting discovery. He has shown that turning off this molecule prevents metastasis. The simple fact is that if you stop metastasis, you stop cancer from killing people. We now need to focus on developing drugs that can block PLCОі1."
'Phospholipase CОі1 is Required for Metastasis Development and Progression' is published in Cancer Research.
The research was supported by The Association for International Cancer Research and by the European Commission FP6 program Apotherapy.
Notes:
Barts and The London School of Medicine and Dentistry
Barts and The London School of Medicine and Dentistry - at Queen Mary, University of London - offers international levels of excellence in research and teaching while serving a population of unrivalled diversity amongst which cases of diabetes, hypertension, heart disease, TB, oral disease and cancers are prevalent, within east London and the wider Thames Gateway. Through partnership with our linked trusts, notably Barts and The London NHS Trust, and our associated University Hospital trusts - Homerton, Newham, Whipps Cross and Queen's - the School's research and teaching is informed by an exceptionally wide ranging and stimulating clinical environment.
At the heart of the School's mission lies world class research, the result of a focused programme of recruitment of leading research groups from the UK and abroad and a ВЈ100 million investment in state-of-the-art facilities. Research is focused on translational research, cancer, cardiology, clinical pharmacology, inflammation, infectious diseases, stem cells, dermatology, gastroenterology, haematology, diabetes, neuroscience, surgery and dentistry.
The School is nationally and internationally recognised for research in these areas, reflected in the ВЈ40 million it attracts annually in research income. Its fundamental mission, with its partner NHS Trusts, and other partner organisations such as CRUK, is to ensure that that the best possible clinical service is underpinned by the very latest developments in scientific and clinical teaching, training and research.
Source: Alex Fernandes
Queen Mary, University of London
воскресенье, 5 июня 2011 г.
In 'Biopsy' Tests Wireless Microgrippers Grab Living Cells
In experiments that pave the way for tiny mobile surgical tools activated by heat or chemicals, Johns Hopkins researchers have invented dust-particle-size devices that can be used to grab and remove living cells from hard-to-reach places without the need for electrical wires, tubes or batteries. Instead, the devices are actuated by thermal or biochemical signals.
The mass-producible microgrippers each measure approximately one-tenth of a millimeter in diameter. In lab tests, they have been used to perform a biopsy-like procedure on animal tissue placed at the end of a narrow tube. Experiments using the devices were reported in the online Early Edition of Proceedings of the National Academy of Sciences for the week of Jan. 12-16.
Although the devices will require further refinement before they can be used in humans, David H. Gracias, who supervised the project, said these thermobiochemically responsive, functional micro-tools represent a paradigm shift in engineering. "We've demonstrated tiny inexpensive tools that can be triggered en masse by nontoxic biochemicals," said Gracias, an assistant professor of chemical and biomolecular engineering in Johns Hopkins' Whiting School of Engineering. "This is an important first step toward creating a new set of biochemically responsive and perhaps even autonomous micro- and nanoscale surgical tools that could help doctors diagnose illnesses and administer treatment in a more efficient, less invasive way."
Today, doctors who wish to collect cells or manipulate a bit of tissue inside a patient's body often use tethered microgrippers connected to thin wires or tubes. But these tethers can make it difficult navigate the tool through tortuous or hard-to-reach locations. To eliminate this problem, the untethered grippers devised by Gracias' team contain gold-plated nickel, allowing them to be steered by magnets outside the body. "With this method, we were able to remotely move the microgrippers a relatively long distance over tissue without getting stuck, he said. "Additionally, the microgrippers are triggered to close and extricate cells from tissue when exposed to certain biochemicals or biologically relevant temperatures."
The microgripper design -- six three-jointed digits extended from a central "palm" -- resembles a crab. (In fact, the joint design was inspired by that of arthropod animals.) To fabricate the microgrippers in their initial flat position with all digits fully extended, the researchers employ photolithography, the same process used to make computer chips. When the tiny devices are inserted in the body and moved magnetically, the gold-plated nickel in the palm and digits will allow doctors to see and guide the grippers with medical imaging units such as an MRI or CT.
The microgrippers' grasping ability is rooted in the chemical composition of the joints embedded in the finger-like digits. These joints contain thin layers of chromium and copper with stress characteristics that would normally cause the digits to curl themselves closed like fingers clasping a baseball. But the researchers added a polymer resin, giving the joints rigidity to keep the fingers from closing.
When the microgrippers arrive at their destination, however, the researchers raise the temperature to 40 degrees C (or 104 degrees F, equivalent to a moderate fever in humans). This heat softens the polymer in the joints, causing the fingers to flex shut. The researchers also found an alternative method: Some nontoxic biological solutions can also weaken the polymer and cause the grippers to clamp down on their target.
In their lab experiments, the Johns Hopkins researchers used a microgripper, guided by a magnet, to grab and transport a dyed bead from among a group of colorless beads in a water solution. Team members also captured dozens of live animal cells from a cell mass at the end of a capillary tube. The cells were still alive 72 hours later, indicating the capture process did not injure them. Also, the microgrippers captured samples from relatively tough bovine bladder tissue.
The experiments showed that the tetherless microgripper concept is viable and has great potential for medical applications, the researchers said. Gracias' team is now working to overcome some remaining hurdles. As currently designed, each biologically compatible gripper can close on a target only once and cannot be reactivated to reopen and release its contents. (A similar device from the Gracias team, aimed at industrial micro-assembly applications, can be directed to both capture and release its load, but this requires chemicals that are not safe for patients. This pick-and-place microgripper was described in a recent article in the Journal of the American Chemical Society.)
Gracias, who also is affiliated with the Institute for NanoBioTechnology at Johns Hopkins, hopes to collaborate with medical researchers who can help to move the microgrippers closer to use as practical biopsy and drug delivery tools in humans. In September, he received a $1.5 million New Innovators Award from the National Institutes of Health. He plans to use the five-year grant to develop an entire mobile, biochemically responsive micro- and nanoscale surgical tool kit.
The lead author of the PNAS microgripper article was Timothy G. Leong, who was a doctoral student supervised by Gracias. In addition to Leong and Gracias, the paper's co-authors, all students supervised by Gracias at Johns Hopkins, were Christina L. Randall, a doctoral student in the Department of Biomedical Engineering; Brian R. Benson, a junior undergraduate supported by a Provost's Undergraduate Research Award; Noy Bassik, who is enrolled in an M.D./Ph.D. program involving the School of Medicine and the Department of Chemical and Biomolecular Engineering; and George M. Stern, a master's degree student in chemical and biomolecular engineering.
The Johns Hopkins Technology Transfer staff has obtained a provisional United States patent covering the team's inventions and is seeking international patent protection.
Funding for the research was provided by the National Science Foundation, the National Institutes of Health, and the Dreyfus and Beckman foundations.
Photos, illustrations and videos may be seen online at jhu/news/home09/jan09/gracias.html.
Related links:
David Gracias' Lab Page: jhu/chembe/gracias/
Department of Chemical and Biomolecular Engineering: jhu/chembe/PNAS:
"Tetherless Thermo-biochemically Actuated Microgrippers: eurekalert/pio/tipsheetdoc.php/237/zpq6355.pdf
Journal of the American Chemical Society: "Pick-and-Place Using Chemically
Actuated Microgrippers": pubs.acs/doi/abs/10.1021/ja806961p
Source: Phil Sneiderman
Johns Hopkins University
The mass-producible microgrippers each measure approximately one-tenth of a millimeter in diameter. In lab tests, they have been used to perform a biopsy-like procedure on animal tissue placed at the end of a narrow tube. Experiments using the devices were reported in the online Early Edition of Proceedings of the National Academy of Sciences for the week of Jan. 12-16.
Although the devices will require further refinement before they can be used in humans, David H. Gracias, who supervised the project, said these thermobiochemically responsive, functional micro-tools represent a paradigm shift in engineering. "We've demonstrated tiny inexpensive tools that can be triggered en masse by nontoxic biochemicals," said Gracias, an assistant professor of chemical and biomolecular engineering in Johns Hopkins' Whiting School of Engineering. "This is an important first step toward creating a new set of biochemically responsive and perhaps even autonomous micro- and nanoscale surgical tools that could help doctors diagnose illnesses and administer treatment in a more efficient, less invasive way."
Today, doctors who wish to collect cells or manipulate a bit of tissue inside a patient's body often use tethered microgrippers connected to thin wires or tubes. But these tethers can make it difficult navigate the tool through tortuous or hard-to-reach locations. To eliminate this problem, the untethered grippers devised by Gracias' team contain gold-plated nickel, allowing them to be steered by magnets outside the body. "With this method, we were able to remotely move the microgrippers a relatively long distance over tissue without getting stuck, he said. "Additionally, the microgrippers are triggered to close and extricate cells from tissue when exposed to certain biochemicals or biologically relevant temperatures."
The microgripper design -- six three-jointed digits extended from a central "palm" -- resembles a crab. (In fact, the joint design was inspired by that of arthropod animals.) To fabricate the microgrippers in their initial flat position with all digits fully extended, the researchers employ photolithography, the same process used to make computer chips. When the tiny devices are inserted in the body and moved magnetically, the gold-plated nickel in the palm and digits will allow doctors to see and guide the grippers with medical imaging units such as an MRI or CT.
The microgrippers' grasping ability is rooted in the chemical composition of the joints embedded in the finger-like digits. These joints contain thin layers of chromium and copper with stress characteristics that would normally cause the digits to curl themselves closed like fingers clasping a baseball. But the researchers added a polymer resin, giving the joints rigidity to keep the fingers from closing.
When the microgrippers arrive at their destination, however, the researchers raise the temperature to 40 degrees C (or 104 degrees F, equivalent to a moderate fever in humans). This heat softens the polymer in the joints, causing the fingers to flex shut. The researchers also found an alternative method: Some nontoxic biological solutions can also weaken the polymer and cause the grippers to clamp down on their target.
In their lab experiments, the Johns Hopkins researchers used a microgripper, guided by a magnet, to grab and transport a dyed bead from among a group of colorless beads in a water solution. Team members also captured dozens of live animal cells from a cell mass at the end of a capillary tube. The cells were still alive 72 hours later, indicating the capture process did not injure them. Also, the microgrippers captured samples from relatively tough bovine bladder tissue.
The experiments showed that the tetherless microgripper concept is viable and has great potential for medical applications, the researchers said. Gracias' team is now working to overcome some remaining hurdles. As currently designed, each biologically compatible gripper can close on a target only once and cannot be reactivated to reopen and release its contents. (A similar device from the Gracias team, aimed at industrial micro-assembly applications, can be directed to both capture and release its load, but this requires chemicals that are not safe for patients. This pick-and-place microgripper was described in a recent article in the Journal of the American Chemical Society.)
Gracias, who also is affiliated with the Institute for NanoBioTechnology at Johns Hopkins, hopes to collaborate with medical researchers who can help to move the microgrippers closer to use as practical biopsy and drug delivery tools in humans. In September, he received a $1.5 million New Innovators Award from the National Institutes of Health. He plans to use the five-year grant to develop an entire mobile, biochemically responsive micro- and nanoscale surgical tool kit.
The lead author of the PNAS microgripper article was Timothy G. Leong, who was a doctoral student supervised by Gracias. In addition to Leong and Gracias, the paper's co-authors, all students supervised by Gracias at Johns Hopkins, were Christina L. Randall, a doctoral student in the Department of Biomedical Engineering; Brian R. Benson, a junior undergraduate supported by a Provost's Undergraduate Research Award; Noy Bassik, who is enrolled in an M.D./Ph.D. program involving the School of Medicine and the Department of Chemical and Biomolecular Engineering; and George M. Stern, a master's degree student in chemical and biomolecular engineering.
The Johns Hopkins Technology Transfer staff has obtained a provisional United States patent covering the team's inventions and is seeking international patent protection.
Funding for the research was provided by the National Science Foundation, the National Institutes of Health, and the Dreyfus and Beckman foundations.
Photos, illustrations and videos may be seen online at jhu/news/home09/jan09/gracias.html.
Related links:
David Gracias' Lab Page: jhu/chembe/gracias/
Department of Chemical and Biomolecular Engineering: jhu/chembe/PNAS:
"Tetherless Thermo-biochemically Actuated Microgrippers: eurekalert/pio/tipsheetdoc.php/237/zpq6355.pdf
Journal of the American Chemical Society: "Pick-and-Place Using Chemically
Actuated Microgrippers": pubs.acs/doi/abs/10.1021/ja806961p
Source: Phil Sneiderman
Johns Hopkins University
суббота, 4 июня 2011 г.
Magnetic Resonance Imaging Program In Small Animal Facility Furthers Research
When powerful magnets line up the body's protons before radiofrequency waves can grab their attention away, it's called spin physics.
When signals generated by the movement are mathematically transformed into dramatic images of hearts, lungs and other organs it's called a magnetic resonance image. "Protons normally would be pointing in many different directions," says Dr. Tom Hu, director of the Small Animal Imaging Program at the Medical College of Georgia. "But if you put an object in the MRI, the magnet will line up the protons and what that does is generate the original, steady state. Then, by applying different radio frequencies, pretty much like what you do with a car antenna, you can pursue radio frequencies to perturb the system and you pretty much listen to it."
When Dr. Hu, a biochemist and biophysicist, tunes in he sees how calcium moves in and out of heart cells as the heart contracts and relaxes and how that movement doesn't work so well in heart failure, a condition resulting in oversized hearts with difficulty beating.
He's looking at whether the metallic manganese ion, which can travel in the same circles as calcium, can enhance the signal and subsequent images he gets of how calcium can't get back into cells after a heart attack. "Once it's disturbed, the cells die and the myocardium dies and you have scar formation," says Dr. Hu whose ultimate goals include better ways to diagnose and treat heart failure, an increasingly common problem in the United States where improved cardiac treatment means many people are living with their heart disease. "Not only can you look at a living organ, you can also study the molecular aspects of this like the calcium ion," says Dr. Hu who came to MCG in 2005 to start the Small Imaging Program in support of research initiatives, such as his, that have clinical promise.
The MRI that is the program's centerpiece looks like the human version except the cylinder the patient lies in is obviously much smaller. However it has a stronger magnet than typical clinical grade units primarily because the organs of interest are so much smaller, says Dr. Nathan Yanasak, magnetic resonance scientist.
Many standard MRIs are 1.5 Tesla and high-end clinical units are 3 Tesla, a measure of the density and intensity of a magnetic field. MCG's small animal MRI is 7 Tesla, not the strongest magnet available for research but one that enables good quality images of small organs which are comparable to those obtained by clinical machines. "It's pretty close to clinical grade," says Dr. Yanasak. "But since you are scanning something smaller you need a larger field of strength to get the animal images to look like a human image," he says. The smallest heart they've imaged, for example, is that of a 3-gram mouse (that's a .105-ounce mouse). "It is better resolution in the sense that you have to have better resolution to see a brain this big," Dr. Yanasak says, holding his fingers very close together.
The textbook answer for why scientists need high-tech imaging studies -- "They are noninvasive, says Dr. Hu, which obviously makes them excellent clinical tools as well. "If you have an animal disease model, for pretty much any noninvasive technique, the advantage is it reduces animal use tremendously," he says.
Like physicians do with patients, basic scientists now use technology to help monitor disease progression over time and even to see if treatments work. In his own work, for example, Dr. Hu watches development of heart failure by monitoring changes in calcium dynamic and heart structure.
Newer technology, on loan to the facility from Xenogen Corp, part of Caliber Life Sciences Corp., has enabled the lab to throw genetic expression into the mix. The optical scanning system uses luciferase, the same enzyme fireflies use to glow, to identify gene expression.
"If you combine (luciferase) with certain genes and the genes are expressed, they glow," says Dr. Hu. "For example, after a heart attack, you can look and see if certain genes are up-regulated, such as inflammatory genes. Now we take the same animal model back to the MRI machine and track how many cells have moved to the site of injury. So, we can combine the information and say, okay, potentially those cells that have been mobilized are due to the gene expression. We can try and link cause and effect so it becomes more of a valuable image," says Dr. Hu. Right now he and Dr. Yanasak are fine-tuning how to make MRI and optical scanning work optimally together and how to also quantify gene expression.
The number of MCG scientists using the facility is significant and growing, says its director. Dr. Adviye Ergul, for example, is looking at blood flow in the brain of her diabetes model and Dr. William Hill is looking at stroke event and recovery.
"We are very open to any interesting ideas that generate interesting scientific data or grant funding opportunities," says Dr. Hu. Goals include becoming an MCG core laboratory facility and adding a small animal PET scanner and ultrasound.
Source: Toni Baker
Medical College of Georgia
When signals generated by the movement are mathematically transformed into dramatic images of hearts, lungs and other organs it's called a magnetic resonance image. "Protons normally would be pointing in many different directions," says Dr. Tom Hu, director of the Small Animal Imaging Program at the Medical College of Georgia. "But if you put an object in the MRI, the magnet will line up the protons and what that does is generate the original, steady state. Then, by applying different radio frequencies, pretty much like what you do with a car antenna, you can pursue radio frequencies to perturb the system and you pretty much listen to it."
When Dr. Hu, a biochemist and biophysicist, tunes in he sees how calcium moves in and out of heart cells as the heart contracts and relaxes and how that movement doesn't work so well in heart failure, a condition resulting in oversized hearts with difficulty beating.
He's looking at whether the metallic manganese ion, which can travel in the same circles as calcium, can enhance the signal and subsequent images he gets of how calcium can't get back into cells after a heart attack. "Once it's disturbed, the cells die and the myocardium dies and you have scar formation," says Dr. Hu whose ultimate goals include better ways to diagnose and treat heart failure, an increasingly common problem in the United States where improved cardiac treatment means many people are living with their heart disease. "Not only can you look at a living organ, you can also study the molecular aspects of this like the calcium ion," says Dr. Hu who came to MCG in 2005 to start the Small Imaging Program in support of research initiatives, such as his, that have clinical promise.
The MRI that is the program's centerpiece looks like the human version except the cylinder the patient lies in is obviously much smaller. However it has a stronger magnet than typical clinical grade units primarily because the organs of interest are so much smaller, says Dr. Nathan Yanasak, magnetic resonance scientist.
Many standard MRIs are 1.5 Tesla and high-end clinical units are 3 Tesla, a measure of the density and intensity of a magnetic field. MCG's small animal MRI is 7 Tesla, not the strongest magnet available for research but one that enables good quality images of small organs which are comparable to those obtained by clinical machines. "It's pretty close to clinical grade," says Dr. Yanasak. "But since you are scanning something smaller you need a larger field of strength to get the animal images to look like a human image," he says. The smallest heart they've imaged, for example, is that of a 3-gram mouse (that's a .105-ounce mouse). "It is better resolution in the sense that you have to have better resolution to see a brain this big," Dr. Yanasak says, holding his fingers very close together.
The textbook answer for why scientists need high-tech imaging studies -- "They are noninvasive, says Dr. Hu, which obviously makes them excellent clinical tools as well. "If you have an animal disease model, for pretty much any noninvasive technique, the advantage is it reduces animal use tremendously," he says.
Like physicians do with patients, basic scientists now use technology to help monitor disease progression over time and even to see if treatments work. In his own work, for example, Dr. Hu watches development of heart failure by monitoring changes in calcium dynamic and heart structure.
Newer technology, on loan to the facility from Xenogen Corp, part of Caliber Life Sciences Corp., has enabled the lab to throw genetic expression into the mix. The optical scanning system uses luciferase, the same enzyme fireflies use to glow, to identify gene expression.
"If you combine (luciferase) with certain genes and the genes are expressed, they glow," says Dr. Hu. "For example, after a heart attack, you can look and see if certain genes are up-regulated, such as inflammatory genes. Now we take the same animal model back to the MRI machine and track how many cells have moved to the site of injury. So, we can combine the information and say, okay, potentially those cells that have been mobilized are due to the gene expression. We can try and link cause and effect so it becomes more of a valuable image," says Dr. Hu. Right now he and Dr. Yanasak are fine-tuning how to make MRI and optical scanning work optimally together and how to also quantify gene expression.
The number of MCG scientists using the facility is significant and growing, says its director. Dr. Adviye Ergul, for example, is looking at blood flow in the brain of her diabetes model and Dr. William Hill is looking at stroke event and recovery.
"We are very open to any interesting ideas that generate interesting scientific data or grant funding opportunities," says Dr. Hu. Goals include becoming an MCG core laboratory facility and adding a small animal PET scanner and ultrasound.
Source: Toni Baker
Medical College of Georgia
пятница, 3 июня 2011 г.
Breast Cancer Stem Cells Identified And Repressed In Mouse Tissue
By manipulating highly specific gene-regulating molecules called microRNAs, scientists at Cold Spring Harbor Laboratory (CSHL) report that they have succeeded in singling out and repressing stem-like cells in mouse breast tissue - cells that are widely thought to give rise to cancer.
"If certain forms of breast cancer do indeed have their origin in wayward stem cells, as we believe to be the case, then it is critical to find ways to selectively attack that tumor-initiating population," said Gregory Hannon, Ph.D., CSHL professor and Howard Hughes Medical Institute Investigator. Hannon also is head of a lab focusing on small-RNA research at CSHL and corresponding author of a paper reporting the new research, published in the latest issue of Genes and Development.
"We have shown that a microRNA called let-7, whose expression has previously been associated with tumor suppression, can be delivered to a sample of breast-tissue cells, where it can help us to distinguish stem-like tumor-initiating cells from other, more fully developed cells in the sample. Even more exciting, we found that by expressing let-7 in the sample, we were able to attack and essentially eliminate, very specifically, just that subpopulation of potentially dangerous progenitor cells."
The study was done in collaboration with Senthil Muthuswamy Ph.D., an expert in breast cancer research who heads a CSHL lab focusing on understanding the changes in the biology of breast epithelial cells during the initiation and progression of cancer. Dr. Muthuswamy emphasized that a key ingredient that made this study successful is the use of a mouse breast-derived model cell system called COMMA-1D that not only includes differentiated cells but also stem-like progenitors, in varying stages of maturity, or differentiation.
Unexpected Impact of Conventional Chemotherapy
No therapies currently exist that target stem-like tumor-initiating cells, whose existence in diverse tissues including breast, lung, brain and colon, as well as in the blood, has been demonstrated in a line of research stretching back to 2001. In that year, John E. Dick of the University of Toronto identified cancer stem cells in the blood of leukemia patients.
The cancer stem cell hypothesis is controversial, in part, because of the challenge it represents for current cancer therapy, which regards all tumor cells as potentially capable of spreading the disease, and which seeks to reduce tumor mass and destroy the maximum possible number of tumor cells. In the cancer stem cell hypothesis, reduction of tumor volume alone will not suffice if the stem cells which originally gave rise to the cancer are not specifically targeted and destroyed.
The new Cold Spring Harbor Laboratory research not only suggests one possible way of accomplishing this therapeutic goal - the Hannon lab is initiating a demonstration study in mice - but it also demonstrated that one component of a chemotherapy cocktail currently used as first-line therapy against certain kinds of breast cancer has the potential to actually enrich the subpopulation of stem-like cells that serve as cancer progenitors.
"We found that administration of cyclophosphamide in our mouse cell sample had the effect of enriching for these cells," Hannon said, "which suggests that we need to look carefully at these therapies in model systems to see if the effects we see in cell culture are mirrored in real tumors - and then, to gauge what effect that has on metastasis and relapse following therapy."
It has been known for some time that stem and progenitor cells possess unique defenses, as compared with mature, or differentiated cells, which, unlike their stem-like "mothers" do not have the capacity to renew themselves or to generate multiple cell-types. Stem cells, for instance, are thought to be able to "pump" toxins out of their cellular domain, much as do fully differentiated tumor cells that have developed resistance to chemotherapy.
"A Role for microRNAs in Maintenance of Mouse Mammary Epithelial Progenitor Cells" appears in Genes and Development on December 15, 2007. The complete citation is as follows: Ingrid Ibarra, Yaniv Erlich, Senthil K. Muthuswamy, Ravi Sachidanandam, and Gregory Hannon. Click here to access the paper online.
Cold Spring Harbor Laboratory (CSHL) is a private, non-profit research and education institution dedicated to exploring molecular biology and genetics in order to advance the understanding and ability to diagnose and treat cancers, neurological diseases, and other causes of human suffering.
For more information, visit cshl/.
Source: Jim Bono
Cold Spring Harbor Laboratory
"If certain forms of breast cancer do indeed have their origin in wayward stem cells, as we believe to be the case, then it is critical to find ways to selectively attack that tumor-initiating population," said Gregory Hannon, Ph.D., CSHL professor and Howard Hughes Medical Institute Investigator. Hannon also is head of a lab focusing on small-RNA research at CSHL and corresponding author of a paper reporting the new research, published in the latest issue of Genes and Development.
"We have shown that a microRNA called let-7, whose expression has previously been associated with tumor suppression, can be delivered to a sample of breast-tissue cells, where it can help us to distinguish stem-like tumor-initiating cells from other, more fully developed cells in the sample. Even more exciting, we found that by expressing let-7 in the sample, we were able to attack and essentially eliminate, very specifically, just that subpopulation of potentially dangerous progenitor cells."
The study was done in collaboration with Senthil Muthuswamy Ph.D., an expert in breast cancer research who heads a CSHL lab focusing on understanding the changes in the biology of breast epithelial cells during the initiation and progression of cancer. Dr. Muthuswamy emphasized that a key ingredient that made this study successful is the use of a mouse breast-derived model cell system called COMMA-1D that not only includes differentiated cells but also stem-like progenitors, in varying stages of maturity, or differentiation.
Unexpected Impact of Conventional Chemotherapy
No therapies currently exist that target stem-like tumor-initiating cells, whose existence in diverse tissues including breast, lung, brain and colon, as well as in the blood, has been demonstrated in a line of research stretching back to 2001. In that year, John E. Dick of the University of Toronto identified cancer stem cells in the blood of leukemia patients.
The cancer stem cell hypothesis is controversial, in part, because of the challenge it represents for current cancer therapy, which regards all tumor cells as potentially capable of spreading the disease, and which seeks to reduce tumor mass and destroy the maximum possible number of tumor cells. In the cancer stem cell hypothesis, reduction of tumor volume alone will not suffice if the stem cells which originally gave rise to the cancer are not specifically targeted and destroyed.
The new Cold Spring Harbor Laboratory research not only suggests one possible way of accomplishing this therapeutic goal - the Hannon lab is initiating a demonstration study in mice - but it also demonstrated that one component of a chemotherapy cocktail currently used as first-line therapy against certain kinds of breast cancer has the potential to actually enrich the subpopulation of stem-like cells that serve as cancer progenitors.
"We found that administration of cyclophosphamide in our mouse cell sample had the effect of enriching for these cells," Hannon said, "which suggests that we need to look carefully at these therapies in model systems to see if the effects we see in cell culture are mirrored in real tumors - and then, to gauge what effect that has on metastasis and relapse following therapy."
It has been known for some time that stem and progenitor cells possess unique defenses, as compared with mature, or differentiated cells, which, unlike their stem-like "mothers" do not have the capacity to renew themselves or to generate multiple cell-types. Stem cells, for instance, are thought to be able to "pump" toxins out of their cellular domain, much as do fully differentiated tumor cells that have developed resistance to chemotherapy.
"A Role for microRNAs in Maintenance of Mouse Mammary Epithelial Progenitor Cells" appears in Genes and Development on December 15, 2007. The complete citation is as follows: Ingrid Ibarra, Yaniv Erlich, Senthil K. Muthuswamy, Ravi Sachidanandam, and Gregory Hannon. Click here to access the paper online.
Cold Spring Harbor Laboratory (CSHL) is a private, non-profit research and education institution dedicated to exploring molecular biology and genetics in order to advance the understanding and ability to diagnose and treat cancers, neurological diseases, and other causes of human suffering.
For more information, visit cshl/.
Source: Jim Bono
Cold Spring Harbor Laboratory
четверг, 2 июня 2011 г.
Cell Signaling Glitch Contributes To Lupus Progression
Immune cells that would normally die in healthy people accumulate in bodies of patients who have lupus and contribute to the disease, according to new Saint Louis University research published in the Feb. 15 issue of Immunity.
The finding is important because it tells us more about how lupus develops and suggests a strategy for treating the autoimmune disease, said Harris Perlman, Ph.D., associate professor of molecular microbiology and immunology at Saint Louis University and senior author of the study.
"We want to eliminate those hyperactive immune cells that lead to continuation of the disease but maintain infection-fighting white blood cells," Perlman said. "This will restore the balance of cells in the immune system, which has become very skewed in lupus patients."
It is estimated that between 1.5 and 2 million Americans have some form of lupus, which can damage the kidneys, heart, joints, skin, lungs, blood vessels, liver and nervous system.
In those who have an autoimmune disease such as lupus, the cells in the immune system become confused. Instead of attacking only infected cells or foreign bodies, they turn ultra-vigilant and attack the body's own normal cells and tissues, causing inflammation, pain and injuries.
Perlman and his team have discovered the double whammy for lupus patients. They harbor a higher than normal number of immune cells that carry too much of the pro-survival or anti-apoptotic proteins that tells them to keep living past their prime.
Normally these cells should undergo "apoptosis," a natural process by which cells die so they don't spread infection or take away nutrients from healthy cells. The signal to die can come from inside the cell itself or from outside the cell.
Perlman and his colleagues found that the communications system that tells immune cells that it's time to die gets turned off in lupus patients and causes immune cells to accumulate in the body. This failure to delete these cells allows the disease to progress, Perlman said.
Perlman's research team took blood from 14 lupus patients and 14 healthy people. Patients with lupus produced more immune cells with too much of the proteins that prolonged cell life. The more of these immune cells patient had, the more severe was his or her disease.
The team used that knowledge to create mice that had a defect in the two known "death pathways" that signal when they're supposed to die. They showed that these mice displayed high numbers of immune cells that would normally die and that all of the mice developed very severe lupus.
"We showed it in patients and reproduced the result in mice," Perlman said. "Now we can use this mouse model to do pre-clinical trials for therapies to fight lupus."
The next step, Perlman said, is to test a therapy that blocks proteins that prevent cells from dying by mimicking the action of proteins that tell immune cells it's time to die.
"We want to deliver a treatment that will target those proteins that keep these immune cells alive. This could induce a type of remission in patients," Perlman said.
"We need to tilt the balance toward the normal cells cells that don't want to attack the body but function correctly so the patient can fight infection and have a normal life. We want to kill those cells that lead to the continuation of disease."
The research was conducted in collaboration with the University of Texas- Southwestern Medical Center, University of California-San Diego and Yale University. It was funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases and National Institute of Allergy and Infectious Diseases, both divisions of the National Institutes of Health, and the autoimmune disease fund provided by Saint Louis University.
Established in 1836, Saint Louis University School of Medicine has the distinction of awarding the first medical degree west of the Mississippi River. The school educates physicians and biomedical scientists, conducts medical research, and provides health care on a local, national and international level. Research at the school seeks new cures and treatments in five key areas: cancer, liver disease, heart/lung disease, aging and brain disease, and infectious disease.
Saint Louis University Medical Center
St. Louis, MO 63103
United States
medschool.slu/index.phtml
The finding is important because it tells us more about how lupus develops and suggests a strategy for treating the autoimmune disease, said Harris Perlman, Ph.D., associate professor of molecular microbiology and immunology at Saint Louis University and senior author of the study.
"We want to eliminate those hyperactive immune cells that lead to continuation of the disease but maintain infection-fighting white blood cells," Perlman said. "This will restore the balance of cells in the immune system, which has become very skewed in lupus patients."
It is estimated that between 1.5 and 2 million Americans have some form of lupus, which can damage the kidneys, heart, joints, skin, lungs, blood vessels, liver and nervous system.
In those who have an autoimmune disease such as lupus, the cells in the immune system become confused. Instead of attacking only infected cells or foreign bodies, they turn ultra-vigilant and attack the body's own normal cells and tissues, causing inflammation, pain and injuries.
Perlman and his team have discovered the double whammy for lupus patients. They harbor a higher than normal number of immune cells that carry too much of the pro-survival or anti-apoptotic proteins that tells them to keep living past their prime.
Normally these cells should undergo "apoptosis," a natural process by which cells die so they don't spread infection or take away nutrients from healthy cells. The signal to die can come from inside the cell itself or from outside the cell.
Perlman and his colleagues found that the communications system that tells immune cells that it's time to die gets turned off in lupus patients and causes immune cells to accumulate in the body. This failure to delete these cells allows the disease to progress, Perlman said.
Perlman's research team took blood from 14 lupus patients and 14 healthy people. Patients with lupus produced more immune cells with too much of the proteins that prolonged cell life. The more of these immune cells patient had, the more severe was his or her disease.
The team used that knowledge to create mice that had a defect in the two known "death pathways" that signal when they're supposed to die. They showed that these mice displayed high numbers of immune cells that would normally die and that all of the mice developed very severe lupus.
"We showed it in patients and reproduced the result in mice," Perlman said. "Now we can use this mouse model to do pre-clinical trials for therapies to fight lupus."
The next step, Perlman said, is to test a therapy that blocks proteins that prevent cells from dying by mimicking the action of proteins that tell immune cells it's time to die.
"We want to deliver a treatment that will target those proteins that keep these immune cells alive. This could induce a type of remission in patients," Perlman said.
"We need to tilt the balance toward the normal cells cells that don't want to attack the body but function correctly so the patient can fight infection and have a normal life. We want to kill those cells that lead to the continuation of disease."
The research was conducted in collaboration with the University of Texas- Southwestern Medical Center, University of California-San Diego and Yale University. It was funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases and National Institute of Allergy and Infectious Diseases, both divisions of the National Institutes of Health, and the autoimmune disease fund provided by Saint Louis University.
Established in 1836, Saint Louis University School of Medicine has the distinction of awarding the first medical degree west of the Mississippi River. The school educates physicians and biomedical scientists, conducts medical research, and provides health care on a local, national and international level. Research at the school seeks new cures and treatments in five key areas: cancer, liver disease, heart/lung disease, aging and brain disease, and infectious disease.
Saint Louis University Medical Center
St. Louis, MO 63103
United States
medschool.slu/index.phtml
среда, 1 июня 2011 г.
Impact Of Insulin Receptor Signaling Upon Synapses And Dendrites Shown For The First Time In Living Creatures
A team of neuroscientists at Cold Spring Harbor Laboratory (CSHL) has demonstrated for the first time in living animals that insulin receptors in the brain can initiate signaling that regulates both the structure and function of neural circuits.
The finding suggests a significant role for this class of receptors and perhaps for insulin, not only in brain development, but also in cognition and in pathological processes in which cognition is impaired, as in Alzheimer's disease, for example.
Insulin receptors on the surface of cells throughout the body have long been understood to play a central role in controlling metabolism through the regulation of glucose. When a molecule of insulin, a hormone, "docks" with the receptor, a complex signaling cascade is set in motion inside a cell, culminating in the cell's uptake of insulin.
The Brain Is Not "Insulin-Insensitive" After All
Although insulin receptors are observed in certain parts of the mammalian brain, most scientists, until a few years ago, had assumed the organ was "insulin-insensitive," knowing that glucose could be taken up by brain cells without the involvement of either insulin or insulin receptors.
In recent years, however, it has been shown that the brain is indeed an insulin target, and in cell-culture experiments that insulin receptor signaling in neurons can have an impact on the formation and development of neural circuits. This had never been demonstrated in living organisms until it was shown in experiments performed in the laboratory of CSHL Professor Hollis Cline, Ph.D., and reported this week in the journal Neuron.
These experiments, in Xenopus tadpoles, show that insulin receptor signaling in neurons regulates the maintenance of synapses, contributes to the processing of sensory information and is also involved in adjusting the plasticity of brain circuits in response to experience. The latter function is particularly interesting, notes Dr. Cline, since "it is required for the incorporation of neurons into brain circuits."
Blocking the Receptor
To test the idea that insulin receptor signaling regulates the formation of brain circuits during development, the Cold Spring Harbor team used two different techniques to block the function of the receptor in neurons located in the visual pathway of tadpoles. One method "knocked down" expression of the receptors genetically, while the other left them in place but prevented them from initiating signaling cascades within the cell.
"Tadpoles are wonderful creatures for such experiments," Dr. Cline explained, "in part because they have translucent bodies, which makes it easy for us to visualize and record what happens to individual neurons as we manipulate the insulin receptors on their surface."
When insulin receptor function was blocked, neurons in the visual pathway connecting the tadpole's retina to a brain region called the tectum responded very poorly to light stimuli. The tectum is the area in which brain cells process incoming visual signals. "We showed that the insulin receptor is critical for the proper operation of this circuit, and also that defects in receptor signaling cause a reduction in the animal's visual responses," Dr. Cline said.
Time-Lapse Images of Dendritic Branching
The team went on to perform other experiments that demonstrated two remarkable facts. One is that insulin receptor signaling correlates with the density of the synapses, or neuron-to-neuron connections, in brain circuits. In more technical terms, they found that insulin receptors maintain synaptic density and that synapse density decreases when insulin receptors are removed or dysfunctional.
The team also secured time-lapse images of dendritic formations, the ethereal, branch-like structures that receive chemical signals sent from one neuron to the next. Again, they found that when insulin receptors are engaged and sending signals inside the neuron, dendritic growth is enhanced, specifically in response to visual stimulation.
In this, as in the findings about synaptic density, the team found that insulin receptor signaling regulates the form and function of brain circuits in response to incoming visual information. Another way to put this is that the receptor regulates brain circuits in response to "experience."
Possible Links to Disease
This suggests that insulin receptors in the brain may play a key role not only in the brain's development early in life, but also in disease processes that usually occur late in life. People with advanced diabetes suffer memory loss and cognitive deficits, possibly because insulin receptor signaling in the brain is disrupted, synaptic connections are lost and brain circuits don't work optimally.
In addition, other researchers have found a correlation between diminished insulin receptor signaling and Alzheimer's disease. Results of the Cold Spring Harbor team's research raise the question of whether deficits in learning and memory associated with Alzheimer's might be linked causally to decreased synaptic density as a consequence of lowered insulin receptor signaling. "We are a long way from knowing this for sure, but it's the direction in which our work now takes us," Dr. Cline said.
"Insulin Receptor Signaling Regulates Synapse Number, Dendritic Plasticity, and Circuit Function In Vivo" appeared in Neuron on June 11, 2008. The complete citation is as follows: Shu-Ling Chiu, Chih-Ming Chen and Hollis T. Cline. Click here to access the paper online.
Cold Spring Harbor Laboratory (CSHL) is a private, nonprofit research and education institution dedicated to exploring molecular biology and genetics to advance the understanding and ability to diagnose and treat cancers, neurological diseases and other causes of human suffering.
For more information, visit cshl/.
Source: Jim Bono
Cold Spring Harbor Laboratory
The finding suggests a significant role for this class of receptors and perhaps for insulin, not only in brain development, but also in cognition and in pathological processes in which cognition is impaired, as in Alzheimer's disease, for example.
Insulin receptors on the surface of cells throughout the body have long been understood to play a central role in controlling metabolism through the regulation of glucose. When a molecule of insulin, a hormone, "docks" with the receptor, a complex signaling cascade is set in motion inside a cell, culminating in the cell's uptake of insulin.
The Brain Is Not "Insulin-Insensitive" After All
Although insulin receptors are observed in certain parts of the mammalian brain, most scientists, until a few years ago, had assumed the organ was "insulin-insensitive," knowing that glucose could be taken up by brain cells without the involvement of either insulin or insulin receptors.
In recent years, however, it has been shown that the brain is indeed an insulin target, and in cell-culture experiments that insulin receptor signaling in neurons can have an impact on the formation and development of neural circuits. This had never been demonstrated in living organisms until it was shown in experiments performed in the laboratory of CSHL Professor Hollis Cline, Ph.D., and reported this week in the journal Neuron.
These experiments, in Xenopus tadpoles, show that insulin receptor signaling in neurons regulates the maintenance of synapses, contributes to the processing of sensory information and is also involved in adjusting the plasticity of brain circuits in response to experience. The latter function is particularly interesting, notes Dr. Cline, since "it is required for the incorporation of neurons into brain circuits."
Blocking the Receptor
To test the idea that insulin receptor signaling regulates the formation of brain circuits during development, the Cold Spring Harbor team used two different techniques to block the function of the receptor in neurons located in the visual pathway of tadpoles. One method "knocked down" expression of the receptors genetically, while the other left them in place but prevented them from initiating signaling cascades within the cell.
"Tadpoles are wonderful creatures for such experiments," Dr. Cline explained, "in part because they have translucent bodies, which makes it easy for us to visualize and record what happens to individual neurons as we manipulate the insulin receptors on their surface."
When insulin receptor function was blocked, neurons in the visual pathway connecting the tadpole's retina to a brain region called the tectum responded very poorly to light stimuli. The tectum is the area in which brain cells process incoming visual signals. "We showed that the insulin receptor is critical for the proper operation of this circuit, and also that defects in receptor signaling cause a reduction in the animal's visual responses," Dr. Cline said.
Time-Lapse Images of Dendritic Branching
The team went on to perform other experiments that demonstrated two remarkable facts. One is that insulin receptor signaling correlates with the density of the synapses, or neuron-to-neuron connections, in brain circuits. In more technical terms, they found that insulin receptors maintain synaptic density and that synapse density decreases when insulin receptors are removed or dysfunctional.
The team also secured time-lapse images of dendritic formations, the ethereal, branch-like structures that receive chemical signals sent from one neuron to the next. Again, they found that when insulin receptors are engaged and sending signals inside the neuron, dendritic growth is enhanced, specifically in response to visual stimulation.
In this, as in the findings about synaptic density, the team found that insulin receptor signaling regulates the form and function of brain circuits in response to incoming visual information. Another way to put this is that the receptor regulates brain circuits in response to "experience."
Possible Links to Disease
This suggests that insulin receptors in the brain may play a key role not only in the brain's development early in life, but also in disease processes that usually occur late in life. People with advanced diabetes suffer memory loss and cognitive deficits, possibly because insulin receptor signaling in the brain is disrupted, synaptic connections are lost and brain circuits don't work optimally.
In addition, other researchers have found a correlation between diminished insulin receptor signaling and Alzheimer's disease. Results of the Cold Spring Harbor team's research raise the question of whether deficits in learning and memory associated with Alzheimer's might be linked causally to decreased synaptic density as a consequence of lowered insulin receptor signaling. "We are a long way from knowing this for sure, but it's the direction in which our work now takes us," Dr. Cline said.
"Insulin Receptor Signaling Regulates Synapse Number, Dendritic Plasticity, and Circuit Function In Vivo" appeared in Neuron on June 11, 2008. The complete citation is as follows: Shu-Ling Chiu, Chih-Ming Chen and Hollis T. Cline. Click here to access the paper online.
Cold Spring Harbor Laboratory (CSHL) is a private, nonprofit research and education institution dedicated to exploring molecular biology and genetics to advance the understanding and ability to diagnose and treat cancers, neurological diseases and other causes of human suffering.
For more information, visit cshl/.
Source: Jim Bono
Cold Spring Harbor Laboratory
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