Showing posts with label development. Show all posts
Showing posts with label development. Show all posts

Monday, 19 August 2013

Sympathetic neurons engage in "cross talk" with cells in the pancreas during early development

Main Category: Diabetes
Article Date: 19 Aug 2013 - 1:00 PDT Current ratings for:
Sympathetic neurons engage in "cross talk" with cells in the pancreas during early development
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The human body is a complicated system of blood vessels, nerves, organs, tissue and cells each with a specific job to do. When all are working together, it's a symphony of form and function as each instrument plays its intended roles.

Biologist Rejji Kuruvilla and her fellow researchers uncovered what happens when one instrument is not playing its part.

Kuruvilla along with graduate students Philip Borden and Jessica Houtz, both from the Biology Department at Johns Hopkins University's Krieger School of Arts and Sciences, and Dr. Steven Leach from the McKusick-Nathans Institute of Genetic Medicine at the Johns Hopkins School of Medicine, recently published a paper in the journal Cell Reports exploring whether "cross-talk" or reciprocal signaling, takes place between the neurons in the sympathetic nervous system and the tissues that the nerves connect to. In this case the targeted tissue called islets, were in the pancreas.

"We knew that sympathetic neurons need molecular signals from the tissues that they connect with, to grow and survive," said Kuruvilla. "What we did not know was whether the neurons would reciprocally signal to the target tissues to instruct them to grow and mature. It made sense to focus on the pancreas because of previous studies done in diabetic animal models where sympathetic nerves within the pancreas were found to retract early on in the disease, suggesting that dysfunction of the nerves could be an early trigger for pancreatic defects."

The researchers spent approximately three years working with lab mice to test the various scenarios in which signaling between sympathetic neurons and islet cells might take place. The experiments focused on what effects removing the sympathetic nerves would have on pancreas development in newborn mice.

Previous studies had shown that pancreatic cells release a signal of their own, a nerve growth protein, that directs the sympathetic nerves toward the pancreas and provides necessary nutrition to sustain the nerves.

In turn, Kuruvilla's team found that in mutant mice, the removal of the sympathetic neurons resulted in deformities in the architecture of the pancreatic islet cells and defects in insulin secretion and glucose metabolism.

Pancreatic islets are highly organized functional micro-organs with a defined size, shape and distinctive arrangement of endocrine cells. It's this marriage of form and function that result in cells clustered close together, that creates greater, more efficient islet cell function.

However, the mutant mice, with their sympathetic neurons removed, had islet formations that were misshapen, sported lesions and developed in a patchy, uneven manner. Because of their dysfunctional islet cell development, postnatal mice did not secrete enough insulin when confronted with high glucose, and had high blood glucose levels as a result. Increased levels of blood glucose in humans is a hallmark of diabetes.

It's known in neuroscience that the neurons in question from the sympathetic nervous system control the body's "flight or fight" response and communicate with connected tissues by releasing a chemical messenger called norepinephrine. The release of norepinephrine also plays an important role in the development and maturation of islets, said Kuruvilla.

Using sympathetic neurons and islet cells grown together in a culture dish, the researchers observed that islet cells move toward the nerves and identified norepinephrine as the nerve signal that causes the movement of the islet cells.

"Seeing how these islet cells were responding to sympathetic neurons both in a dish and the effects of removing the nerves in a whole animal on islet shape and functions were pretty remarkable," said Borden, lead author of the paper. "It was clear to us that sympathetic neurons were key to how islets were developing, something no one else had shown."

Kuruvilla said these studies, identifying sympathetic nerves as a critical player in organizing pancreatic cells during development and influencing their later function, could add to a better understanding of treating diabetes in the future. The research also lends support to the value in considering the importance of external factors such as nerves and blood vessels when transplanting islet cells for the treatment of diabetes in patients.

"This study reveals interactions between two co-developing systems, sympathetic neurons and pancreatic islet cells, that has important implications for peripheral organ development, and for regeneration of these tissues following injury or disease," said Kuruvilla.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our diabetes section for the latest news on this subject. Please use one of the following formats to cite this article in your essay, paper or report:

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'Sympathetic neurons engage in "cross talk" with cells in the pancreas during early development'

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Monday, 5 August 2013

Re-learning how to see: researchers find crucial on-off switch in visual development

Main Category: Eye Health / Blindness
Also Included In: Neurology / Neuroscience
Article Date: 05 Aug 2013 - 0:00 PDT Current ratings for:
Re-learning how to see: researchers find crucial on-off switch in visual development
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A new discovery by a University of Maryland-led research team offers hope for treating "lazy eye" and other serious visual problems that are usually permanent unless they are corrected in early childhood.

Amblyopia afflicts about three percent of the population, and is a widespread cause of vision loss in children. It occurs when both eyes are structurally normal, but mismatched - either misaligned, or differently focused, or unequally receptive to visual stimuli because of an obstruction such as a cataract in one eye.

During the so-called "critical period" when a young child's brain is adapting very quickly to new experiences, the brain builds a powerful neural network connecting the stronger eye to the visual cortex. But the weaker eye gets less stimulation and develops fewer synapses, or points of connection between neurons. Over time the brain learns to ignore the weaker eye. Mild forms of amblyopia such as "lazy eye" result in problems with depth perception. In the most severe form, deprivation amblyopia, a cataract blocks light and starves the eye of visual experiences, significantly altering synaptic development and seriously impairing vision.

Because brain plasticity declines rapidly with age, early diagnosis and treatment of amblyopia is vital, said neuroscientist Elizabeth M. Quinlan, an associate professor of biology at UMD. If the underlying cause of amblyopia is resolved early enough, the child's vision can recover to normal levels. But if the treatment comes after the end of the critical period and the loss of synaptic plasticity, the brain cannot relearn to see with the weaker eye.

"If a child is born with a cataract and it is not removed very early in life, very little can be done to improve vision," Quinlan said. "The severe amblyopia that results is the most difficult to treat. For that reason, science has the most to gain by a better understanding of the underlying mechanisms."

Quinlan, who specializes in studying how communication through the brain's circuits changes over the course of a lifetime, wanted to find out what process controls the timing of the critical period of synaptic plasticity. If researchers could find the neurological on-off switch for the critical period, she reasoned, clinicians could use the information to successfully treat older children and adults.

Researchers in Quinlan's University of Maryland lab teamed up with the laboratory of Alfredo Kirkwood at Johns Hopkins University to address two questions: What are the age boundaries of the critical period for synaptic plasticity, when it comes to determining eye dominance? And what developmental processes are involved?

Experiments in rodents suggested the timing of the critical period is controlled by a specific class of inhibitory neurons, which come into play after a visual stimulus activates excitatory neurons that link the eye to the visual cortex. The inhibitory neurons act as signal controllers, affecting the interactions between excitatory neurons and synapses.

"The generally accepted view has been that as the inhibitory neurons develop, synaptic plasticity declines, which was thought to occur at about five weeks of age in rodents," roughly equivalent to five years of age in humans, Quinlan said. But in earlier experiments, Quinlan and Kirkwood found no correlation between the development of these inhibitory neurons and the loss of plasticity. In fact, they found the visual circuitry in rodents was highly adaptable at ages beyond five weeks.

In their latest research the UMD-led team looked "one synapse upstream from these inhibitory neurons," Quinlan said, studying the control of that synapse by a protein called NARP (Neuronal Activity-Regulated Pentraxin). Working with two sets of mice - one group genetically similar to wild mice and another that lacked the NARP gene - the researchers covered one eye in each animal to simulate conditions that produce amblyopia.

The mice that were genetically similar to wild mice developed amblyopia, with characteristic dominance of the normal eye over the deprived eye. But the mice that lacked NARP did not develop amblyopia, regardless of age or the length of time one eye was deprived of stimulation.

The study, published in the current issue of the peer-reviewed journal Neuron, demonstrated that only one specific class of synapses was affected by the absence of NARP. Without NARP, the mice simply had no critical period in which the brain circuitry was weakened in response to the impaired blocking vision in one eye, Quinlan said. Except for the lack of this plasticity, their vision was normal.

"It's remarkable how specific the deficit is," Quinlan said. Without the NARP protein, "these animals develop normal vision. Their brain circuitry just isn't plastic. We can completely turn off the critical period for plasticity by knocking out this protein."

Since there are indications that NARP levels vary with age, the discovery raises hope that a treatment targeting NARP levels in humans could allow correction of amblyopia late in life, without affecting other aspects of vision.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our eye health / blindness section for the latest news on this subject.

Yu Gu, Shiyong Huang, Michael G. Chang, Paul Worley, Alfredo Kirkwood, and Elizabeth M. Quinlan, “Obligatory Role for the Immediate Early Gene NARP in Critical Period Plasticity,” Neuron 79, 335-346, July 24, 2013

University of Maryland

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Stem cell researchers produce new model of leukemia development

Main Category: Lymphoma / Leukemia / Myeloma
Also Included In: Stem Cell Research
Article Date: 02 Aug 2013 - 1:00 PDT Current ratings for:
Stem cell researchers produce new model of leukemia development
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Eight years ago, two former Stanford University postdoctoral fellows, one of them still in California and the other at the Harvard Stem Cell Institute (HSCI) in Cambridge, began exchanging theories about why patients with leukemia stop producing healthy blood cells. What was it, they asked, that caused bone marrow to stop producing normal blood-producing cells?

And after almost a decade of bicoastal collaboration, Emmanuelle Passegué, now a professor in the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at the University of California, San Francisco, and Amy Wagers, a professor in Harvard's Department of Stem Cell and Regenerative Biology, have the answer.

They have found that cancer stem cells actively remodel the environment of the bone marrow, where blood cells are formed, so that it is hospitable only to diseased cells. This finding could influence the effectiveness of bone marrow transplants, currently the only cure for late-stage leukemia, but with a 25 percent success rate due to repopulation of residual cancer cells.

Their results, which were recently published online in Cell Stem Cell, show that leukemia cells cannot replicate in the bone marrow niche as well as healthy blood-forming stem cells can, so the cancer cells gain the advantage by triggering bone marrow-maintenance cells to deposit collagen and inflammatory proteins, leading to fibrosis - or scarring - of the bone marrow cavity.

"They remodel the microenvironment so that it is basically callous, kicking the normal stem cells out of the bone marrow and encouraging the production of even more leukemic cells," Passegué said. This model is a shift from the widely held theory that cancer cells simply crowd out the healthy cells.

Passegué and Wagers stayed in touch, despite the distance between their laboratories, via annual, two-day, "off-the-record" symposiums of junior investigators at the Harvard Stem Cell Institute and the California Institute for Regenerative Medicine (CIRM). The meetings, which began in 2005 and have continued, require all registrants to keep presentations no longer than 15 minutes and only to discuss unpublished work. "It's sort of Las Vegas rules," Wagers said.

At the second such meeting, Passegué was intrigued by Wagers' cell isolation-based approach to studying the bone marrow niche, the environment where stem cells are found. In the ensuing years, the two scientists swapped protocols, chemical reagents, mice, and even postdoctoral researchers in the pursuit of discovering what causes healthy blood cell dysfunction in leukemia. "Wagers was really involved as a creative spirit in the development of this story," Passegué said.

The observation that leukemia cells can remodel the bone marrow niche parallels work done by HSCI co-director David Scadden of the Harvard-affiliated Massachusetts General Hospital, who demonstrated that particular genetic modifications of bone-forming cells initiate changes in the marrow cavity that suppress normal blood formation and promote the emergence of leukemic cells. "So there's this bidirectional communication that's self-reinforcing, "Wagers said. "And if there's a communication loop like that, you can think about interrupting in many different ways."

Passegué wants to understand how bone-marrow support cells are manipulated to sustain leukemia cells, instead of normal blood cells, in order to design therapies that block these detrimental changes. In the short term, her work could explain why 75 percent of bone marrow transplants are unsuccessful. "A poor niche is likely a very important contributing factor for failure to engraft," she said. Her lab has shown that fibrotic bone marrow conditions can be reversed in as little as a few months by removing the bad-acting maintenance cells, and she is now investigating how to restore the healthy bone marrow environment in leukemia patients.

Passegué and Wagers believe the success of this research reflects the value of scientific partnerships. "Both HSCI and CIRM understand the importance of fostering the open communication and collaboration that drives innovation in science," Wagers said.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our lymphoma / leukemia / myeloma section for the latest news on this subject.

The 2013 HSCI/California Junior Faculty Symposium will take place Nov. 8 and 9 at the University of California, Los Angeles.

Koen Schepers, now at the University Medical Center Utrecht, was the first author on this study. The work was supported by the National Institutes of Health, CIRM, a NWO Rubicon Fellowship, and a KWF Fellowship.

Harvard University

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Study reveals target for drug development for temporomandibular joint disorder (TMJD) - a chronic jaw pain disorder

Main Category: Dentistry
Also Included In: Pain / Anesthetics
Article Date: 05 Aug 2013 - 1:00 PDT Current ratings for:
Study reveals target for drug development for temporomandibular joint disorder (TMJD) - a chronic jaw pain disorder
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Temporomandibular joint disorder (TMJD) is the most common form of oral or facial pain, affecting over 10 million Americans. The chronic disorder can cause severe pain often associated with chewing or biting down, and lacks effective treatments.

In a study in mice, researchers at Duke Medicine identified a protein that is critical to TMJD pain, and could be a promising target for developing treatments for the disorder. Their findings are published in the August issue of the journal PAIN.

Aside from cases related to trauma, little is known about the root cause of TMJD. The researchers focused on TRPV4, an ion channel protein that allows calcium to rapidly enter cells, and its role in inflammation and pain associated with TMJD.

"TRPV4 is widely expressed in sensory neurons found in the trigeminal ganglion, which is responsible for all sensations of the head, face and their associated structures, such as teeth, the tongue and temporomandibular joint," said senior study author Wolfgang Liedtke, M.D., PhD, associate professor of neurology and neurobiology at Duke. "This pattern and the fact that TRPV4 has been found to be involved in response to mechanical stimulation made it a logical target to explore."

The researchers studied both normal mice and mice genetically engineered without the Trpv4 gene (which produces TRPV4 channel protein). They created inflammation in the temporomandibular joints of the mice, and then measured bite force exerted by the mice to assess jaw inflammation and pain, similar to how TMJD pain is gauged in human patients. Given that biting can be painful for those with TMJD, bite force lessens the more it hurts.

The mice without the Trpv4 gene had a smaller reduction in bite force - biting with almost full force - suggesting that they had less pain. In normal mice there was more TRPV4 expressed in trigeminal sensory neurons when inflammation was induced. The increase in TRPV4 corresponded with a greater reduction in bite force.

The researchers also administered a compound to normal mice that blocked TRPV4, and found that inhibiting TRPV4 also led to smaller reductions in bite force, similar to the effects of the mice engineered without the Trpv4 gene.

Surprisingly, the researchers found comparable bone erosion and inflammation in the jaw tissue across all mice, regardless whether the mice had TRPV4 or not.

"Remarkably, the damage is the same but not the pain," Liedtke said. "The mice that had the most TRPV4 appeared to have the most pain, but they all had similar evidence of temporomandibular joint inflammation and bone erosion in the jawbone as a consequence of the inflammation."

The results suggest that TRPV4 and its expression in trigeminal sensory neurons contribute to TMJD pain in mice. Given the lack of effective treatments for this chronic pain disorder, TRPV4 may be an attractive target for developing new therapies.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our dentistry section for the latest news on this subject.

In addition to Liedtke, Duke study authors include senior pain researcher Yong Chen, Ji Hee Hong, Suk Hee Lee, Puja K. Parekh and Carlene Moore of the Department of Neurology; Amy L. McNulty, Nicole E. Rothfusz and Farshid Guilak of the Department of Orthopaedic Surgery; Fan Wang of the Department of Cell Biology/Neurobiology; and Andrea B. Taylor of the Departments of Community and Family Medicine and Evolutionary Anthropology. Susan H. Williams of the Heritage College of Osteopathic Medicine at Ohio University and Robert W. Gereau IV of the Department of Anesthesiology at Washington University in St. Louis also contributed to this research.

The research was supported by the National Institutes of Health (DE018549, DE19440, DE19440S1, NS48602, AR048182 and DE018549-S); Duke Institute for Brain Sciences; Nicholas School of the Environment, Duke University; and Keimyung University School of Medicine in South Korea.

Duke University Medical Center

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'Study reveals target for drug development for temporomandibular joint disorder (TMJD) - a chronic jaw pain disorder'

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Friday, 26 July 2013

Mechanism discovered behind development of autoimmune hepatitis

Main Category: Liver Disease / Hepatitis
Also Included In: Immune System / Vaccines;  Genetics
Article Date: 25 Jul 2013 - 1:00 PDT Current ratings for:
Mechanism discovered behind development of autoimmune hepatitis
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A gene mutation disrupts the activity of certain immune cells and causes the immune system to erroneously attack the liver, according to a new animal study from the Icahn School of Medicine at Mount Sinai. The findings, published in the Journal of Clinical Investigation, will provide a new model for studying drug targets and therapies for Autoimmune Hepatitis (AIH), a condition for which the only treatment options are short-acting steroids or liver transplant.

T-cells, immune cells created in an organ called the thymus, grow into healthy T-cells with the help of medullary thymic epithelial cells (mTECs). mTECs act as coaches to T-cells to teach them when to attack tissue that might be harmful and when to leave it alone. T-cells that attack healthy body tissue are programmed to die. Led by Konstantina Alexandropoulos, PhD, Associate Professor of Medicine in the Division of Clinical Immunology at Mount Sinai, the research team sought to create a model for understanding why certain immune cells called T-cells inappropriately attack healthy tissues in the body, leading to inflammation and autoimmune diseases like lupus, rheumatoid arthritis, and AIH.

Dr. Alexandropoulos and her team, consisting of Anthony Bonito, first author and PhD candidate at Mount Sinai and contributing author Costica Aloman, PhD, former Assistant Professor of Medicine in the Division of Liver Diseases at Mount Sinai, created mutations in a gene called Traf6 in a mouse model, which caused depletion of mTECs. The research team hypothesized that without mTECs to coach them, T-cells would aberrantly attack healthy cells. Surprisingly, while the depletion of mTECs did cause an autoimmune reaction, the T-cells homed directly to the liver and attacked it rather than other healthy tissue.

"We thought that deleting Traf6 would trigger an autoimmune reaction due to a depletion of mTECs, but did not expect the autoimmune response to be specific to the liver," said Dr. Alexandropoulos. "These findings provide an exciting new animal model to study AIH. We hope that this research will pave the way for new therapies to address a significant unmet need for people with this disease."

Dr. Alexandropoulos and her team hope to identify and study compounds or proteins that prevent the depletion of mTECs using cells from humans with AIH. Mount Sinai has one of the largest cohort of patients in the country to support research on liver diseases such as AIH.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our liver disease / hepatitis section for the latest news on this subject.

This research was supported by grants R01 AI49387-01, R56 AI049387-05, and R01 AI068963-01 from the National Institute of Allergy and Infectious Disease, a division of the National Institutes of Health.

The Mount Sinai Hospital / Mount Sinai School of Medicine

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