TAG: "Arthritis"

Childhood syndrome combining lung disease, arthritis is ID’d

Discovery suggests mechanism, possible therapies for severe disorder.

By Pete Farley, UC San Francisco

Using the latest genome sequencing techniques, a research team led by scientists from UC San Francisco, Baylor College of Medicine and Texas Children’s Hospital has identified a new autoimmune syndrome characterized by a combination of severe lung disease and arthritis that currently has no therapy.

The hereditary disorder, which appears in early childhood, had never been diagnosed as a single syndrome. The new research revealed that it is caused by mutations in a single gene that disrupt how proteins are shuttled around within cells. Patients with the newly discovered syndrome have a poor prognosis, and at present can only be treated with anti-inflammatory and immunosuppressant drugs. Many have lung disease so severe that they must receive lung transplants.

Thanks to biological mechanisms revealed in the research, patients could soon have access to a wider range of therapies, according to Anthony K. Shum, M.D., UCSF assistant professor of medicine and co-senior author of the new study. “We believe that there are small molecules in development that can help correctly traffic the proteins that are misdirected in this syndrome, so that’s something we really want to go after.”

Levi B. Watkin, Ph.D., a postdoctoral fellow at Baylor; former UCSF postdoctoral fellow Birthe Jessen, Ph.D.; and Wojciech Wiszniewski, M.D., assistant professor of molecular and human genetics at Baylor, led the research, which is reported in the April online edition of Nature Genetics.

For Shum, the project was sparked when a woman was admitted to the Emergency Department at a California medical center with pulmonary hemorrhage. In the course of treating the patient, Shum learned that she had arthritis as well, and that a sibling and aunt also had both lung disease and arthritis.

Some time later, when Shum encountered the patient’s mother in the hospital’s corridor, she mentioned that a distant cousin she had never met had posted on a social media site that her own 2 1/2-year-old daughter was being treated at another hospital for pulmonary hemorrhage. Shum went to that hospital and found that, in addition to dramatic hemorrhaging in the child’s lungs, she too had arthritis.

With the help of UCSF medical students, Shum began searching for other affected family members and ultimately identified a distant relative in another state with the same syndrome. The group then sequenced DNA samples from nine family members, some with the syndrome and some who are unaffected, to search for mutations that might underlie the disorder.

“We sort of took a flyer,” Shum said. “The likelihood of finding something was low.”

UCSF scientists quickly zeroed in on a region of the genome containing a gene known as COPA, a result in which they initially had little confidence.

COPA mutations were completely unexpected,” Shum said. “The COPA protein is expressed throughout the body, and no diseases associated with this gene had ever been reported.” But an independent genetic analysis produced the same result: using this second method, Shum said, “You’ll usually see peaks spread across the genome, but we only got a single peak. It was highly significant, and COPA was right under it.”

The COPA protein is essential in intracellular transport – the process by which newly made proteins are moved to their proper locations in the cell – and the scientists found that the COPA mutations seen in the patients “cripple the protein,” said Shum, preventing it from performing this vital function.

Encouraged by the consistency and clarity of these results, Shum reached out to physicians at other institutions to see if they had seen patients with the same cluster of symptoms.

“By pure serendipity,” Shum said, he was soon contacted by co-senior author Jordan S. Orange, M.D., Ph.D., director of the Texas Children’s Hospital Center for Human Immunobiology, who had seen similar cases. Moreover, Orange’s colleague, sequencing expert James R. Lupski, M.D., Ph.D., co-senior author and Cullen Professor of Molecular and Human Genetics at Baylor, had independently fingered COPA mutations in his own genomic analyses of these cases.

Ultimately the UCSF-Baylor-Texas Children’s team identified five families in which 30 family members carried deleterious COPA mutations. Only 21 of those carriers were affected by lung and joint problems, suggesting that, although the disease is inherited, it has “incomplete penetrance” – the presence of COPA mutations does not solely determine that an individual will develop the syndrome.

“The fact that we discovered five unrelated families and over 20 affected individuals in just over two and half years of investigating this leads me to believe that this is by no means ultra-rare,” said Orange.

Subsequent experiments with tissue from affected patients revealed that faulty protein trafficking by mutant COPA results in a condition known as “cellular stress,” which in turn sets off an autoimmune reaction mediated by immune-system cells known at Th17 cells.

Because Th17 cells have already implicated in autoimmune diseases, particularly in rheumatoid arthritis, Shum believes that targeting these cells with drugs may provide a new therapeutic avenue for those with the syndrome.

“In our current research we’re making sure that we have a clear mechanism, so we can come up with a potential drug target,” he said.

Orange added that the new research may have ramifications that extend beyond this particular syndrome, especially for arthritis therapies.

“We are excited to learn how variants of this disease might be more broadly applicable and might be instructive to our overall understanding of arthritis,” he said.

In the meantime, Shum said, patients and their families have been gratified that the mysterious condition affecting their families is beginning to be understood.

“When I first contacted the families we located, it was a huge relief to them to know that there are other people like them and that someone is working on this disorder.”

The research was funded by the National Institutes of Health, The Jeffrey Modell Foundation, The Foundation of the American Thoracic Society, The Pulmonary Fibrosis Foundation, and The Nina Ireland Program for Lung Health at UCSF.

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Autoimmune disease strategy emerges from immune cell discovery

UCSF experiments halt pancreas destruction in mouse model of diabetes.

Mark Anderson led a team that identified an immune cell, called eTAC cells (shown in green), that may help prevent autoimmune diseases. ETAC cells, which contain a protein in their nucleus called AIRE (shown in red) are relatively rare, and found in lymph nodes and the spleen.

Mark Anderson led a team that identified an immune cell, called eTAC cells (shown in green), that may help prevent autoimmune diseases. ETAC cells, which contain a protein in their nucleus called AIRE (shown in red) are relatively rare, and found in lymph nodes and the spleen.

Scientists from UC San Francisco have identified a new way to manipulate the immune system that may keep it from attacking the body’s own molecules in autoimmune diseases such as type 1 diabetes, rheumatoid arthritis and multiple sclerosis.

The researchers, led by immunologist Mark Anderson, M.D., Ph.D., a professor with the UCSF Diabetes Center, have discovered a distinctive type of immune cell called an eTAC, which puts a damper on immune responses.

Anderson’s research team found that eTACs reside in lymph nodes and spleen in both humans and mice, and determined that they could be manipulated to stop the destruction of the pancreas in a mouse model of diabetes. The study appears in the September issue of the journal Immunity.

Using green fluorescent protein (GFP) to highlight a key regulatory protein called AIRE, Anderson’s research team tracked down the rare eTACs and their role in a phenomenon known as peripheral tolerance, which helps prevent autoimmune disease throughout the body.

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The mechanics of arthritis

UC Santa Barbara research into friction provides insight.

Jacob Isrealachvili, Xavier Banquy and Dong Woog Lee, UCSB

Jacob Isrealachvili, Xavier Banquy and Dong Woog Lee, UC Santa Barbara

A new, noninvasive and low-cost method for the early detection and monitoring of osteoarthritis (arthritis caused by wear and tear) may be on its way, thanks to research by UC Santa Barbara scientists from the Department of Chemical Engineering and the Department of Materials.

By studying patterns of friction between cartilage pads, the researchers discovered a different type of friction that is more likely to cause wear and damage. Their work suggests ways to detect this friction, and points to new research directions for getting to the root cause of arthritis. The findings are published in the recent issue of the Proceedings of the National Academy of Science.

Imagine going to the doctor for your aching knees. For some, this may involve uncomfortable needle sticks to draw blood for lab tests or the extraction of the fluid surrounding the aching joint. But what if your doctor could actually listen to your body, monitoring the way your knees sound as they bend and flex? Research by Jacob Israelachvili, UCSB professor of chemical engineering and materials science; grad student researcher Dong Woog Lee; and postdoctoral researcher Xavier Banquy says that it’s possible.

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UC Davis scientist receives funding for juvenile arthritis research

Shriners Hospitals for Children provides $1 million in grants to find new treatment targets.

Iannis Adamopoulos, UC Davis

Iannis Adamopoulos, a researcher dedicated to studying diseases of the immune and skeletal systems, has received $1 million in grants from Shriners Hospitals for Children to find new treatment targets for juvenile arthritis — the most common cause of orthopaedic disability among children.

Adamopoulos is an assistant professor of rheumatology, allergy and clinical immunology at UC Davis and principal investigator for the Institute for Pediatric Regenerative Medicine, a research collaboration of the UC Davis School of Medicine and Shriners Hospitals for Children – Northern California. He will use the funding to define the role of leukotriene B4 (LTB4) in juvenile arthritis.

“We have preliminary evidence that LTB4 is found in inflamed joint tissue and stimulates bone destruction through the activation of specialized bone-destroying cells,” said Adamopoulos, who has been investigating inflammatory arthritis for several years. “We think that LTB4 could potentially be a critical factor in juvenile arthritis.”

The funding will also support the research of Hong Qiu, an expert in leukotriene biochemistry and researcher in the Adamopoulos lab, who will test the potential of leukotriene inhibitors in treating juvenile arthritis.

“Collectively, our studies will provide a detailed understanding of the pathogenetic mechanisms of LTB4 and will foster new therapeutic strategies for juvenile arthritis with improved outcomes,” Adamopoulos said.

Juvenile arthritis and related disorders are estimated to affect nearly 300,000 children in the U.S. It causes episodes of joint stiffness and pain that can be accompanied by rashes and fevers at the onset. If experienced long term, the disease can permanently affect a child’s mobility, internal organs and eyesight. Current treatments are only partially effective, highlighting the critical need for new therapies that specifically address arthritis in children.

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Preventing osteoarthritis: How much exercise is just right?

UCSF study shows too little or too much physical activity increases loss of knee cartilage.

Thomas Link, UC San Francisco

Very high and very low levels of physical activity can both accelerate the degeneration of knee cartilage in middle-aged adults, according to a new study presented this week by UC San Francisco researchers.

During the annual meeting of the Radiological Society of North America (RSNA) in Chicago, Thomas M. Link, M.D., PhD, chief of the Musculoskeletal Imaging Section in UCSF’s Department of Radiology and Biomedical Imaging described a study expanding on earlier work that showed an association between physical activity and cartilage degeneration.

Nearly one in every two people in the U.S. may develop knee osteoarthritis by age 85, according to the Centers for Disease Control and Prevention. By 2030, an estimated 67 million Americans over the age of 18 are projected to have physician-diagnosed arthritis.

In the new study, Link and his colleagues looked at changes in knee cartilage among a group of 205 middle-aged adults over a four-year period, taking magnetic resonance imaging (MRI)-based measurements every two years to track early degenerative changes to the cartilage in their knees over time.

The patients were all part of the Osteoarthritis Initiative, an international collaboration working on the prevention and treatment of knee osteoarthritis that is coordinated by UCSF and funded by the National Institutes of Health. They answered questionnaires yearly over four years to correlate their exercise levels with the MRI measurements.

What the researchers found is that the patients who were the most physically active showed accelerated degeneration of knee cartilage over time. Participating frequently in high-impact activities, such as running multiple hours per week, appeared to be associated with a higher risk for development of osteoarthritis. Those who had very low levels of activity also had accelerated degeneration and higher risk.

“Based on these results, moderate physical activity levels appear most beneficial to prevent cartilage degeneration in patients at risk for osteoarthritis,” said Link. “Lower impact sports, such as walking or swimming, are likely more beneficial than higher impact sports, such as running or tennis, in individuals at risk for osteoarthritis.”

At the early stages of osteoarthritis, cartilage changes are reversible, and people who are at higher risk for osteoarthritis because of knee injuries, surgery, a family history of total joint replacement or obesity can reduce their risk for cartilage degeneration by maintaining a healthy weight and avoiding risky activities and strenuous, high-impact exercise, Link said.

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UC Davis bone health expert to lead new research initiative

$7.2M federal grant to establish specialized research center.

Diagram of painful knee

Nancy Lane, professor of internal medicine and the endowed chair of Healthy Aging and Geriatrics at the UC Davis School of Medicine, has been awarded a $7.2 million federal grant to establish a specialized research center at UC Davis’ Sacramento campus to explore the sex differences related to osteoporosis, carpal tunnel syndrome, osteoarthritis, and kyphosis (a condition causing over-curvature of the upper back).

Lane, who is one of the nation’s leading experts in arthritis, osteoporosis and bone health, will lead the collaborative project, which is largely sponsored by the Office of Research on Women’s Health at the National Institutes of Health (NIH). The new center’s overarching goal is to inform and transform preventive efforts and clinical practice in the diagnosis and treatment of musculoskeletal conditions in both sexes. Lane’s groundbreaking translational research has identified active agents in bone that improve bone strength, defined the genetics of musculoskeletal diseases and advanced new therapies for steroid-induced osteoporosis.

“Musculoskeletal diseases are the most frequent ailments that primary-care physicians are now seeing in clinics throughout the United States,” said Lane, who also recently received a $20 million state grant to develop a stem cell therapy for osteoporosis patients and test its effectiveness in clinical trials. “These diseases are not only associated with aging, particularly osteoporosis and osteoarthritis, but they occur more often in women than in men and yet the biologic explanation for this sex difference remains unclear. We plan to vigorously pursue that question and transform both our current preventive efforts and clinical treatments.”

The new center is launching four related studies led by researchers at UC Davis and UC San Francisco. Ellen Gold, professor and chair of the Department of Public Health Sciences at UC Davis, will oversee epidemiology and biostatistics for the project. Expert investigators will conduct studies to explore four specific musculoskeletal syndromes that are known to differ by sex.

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New standards to improve diagnosis of Sjögren’s syndrome

UCSF-led team of international researchers develops criteria to identify autoimmune disease.

Sjögren’s syndrome largely was unknown to the American public until tennis star Venus Williams withdrew from the U.S. Open last year and announced she had the autoimmune disease, in which a person’s white blood cells attack glands that produce tears and saliva.

Now, new guidelines have been developed by an international consortium of researchers, led by those from UC San Francisco, to better support diagnosis and genetics research of Sjögren’s syndrome. It’s the first time the American College of Rheumatology (ACR) has approved classification criteria for the disease.

The criteria are outlined in the article, “American College of Rheumatology Classification Criteria for Sjögren’s Syndrome: A Data-Driven, Expert Consensus Approach in the Sjögren’s International Collaborative Clinical Alliance Cohort,” published in the journal Arthritis Care & Research.

As many as 4 million Americans are living with this disease, according to the Sjögren’s Syndrome Foundation. It’s the second-most common autoimmune rheumatic disease in the United States, with women representing 90 percent of those affected.

The effects from the dryness they experience can be quite significant.

“Tooth decay may be one of the signs which actually makes a dentist suspect that a patient has Sjögren’s syndrome,” said co-lead author of the study Caroline Shiboski, D.D.S, Ph.D., professor of oral medicine at UCSF School of Dentistry. “Such dramatic tooth destruction can be prevented with early diagnosis of salivary hypofunction and prescription of topical fluoride.”

Diagnosis and management of Sjögren’s syndrome requires three areas of specialty practice: rheumatology, ophthalmology and oral medicine/pathology.

Until now, doctors diagnosing the disease relied on a combination of objective tests and subjective features such as patient reports of signs and symptoms.

“Some of the subjective manifestations of Sjögren’s syndrome — dry eyes and dry mouth — are so non-specific,” said Lindsey Criswell, M.D., M.P.H., chief of the UCSF Division of Rheumatology. “In previous years, when those common and non-specific symptoms were part of the classification criteria, some of those patients indeed had Sjögren’s syndrome, but others who met those criteria probably had something else.”

The Sjögren’s International Collaborative Clinical Alliance (SICCA) was created to develop a simpler and more objective criteria set, establishing a universal standard for Sjögren’s syndrome.

“This new criteria set provides more clarity and specificity, which is particularly important for clinical trial enrollment,” said co-lead author Steve Shiboski, Ph.D., professor at the UCSF Division of Biostatistics. “Correct classification of individuals without the disease helps avoid unnecessarily exposing them to potentially toxic side effects of some experimental treatments.”

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UC Davis scientist receives $1.5M grant for rheumatoid arthritis research

Efforts could help to reduce the pain and disability associated with arthritis.

Iannis Adamopoulos, UC Davis

UC Davis researcher Iannis Adamopoulos has received a $1.5 million grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases to study the causes of rheumatoid arthritis — a chronic disease that affects people of all ages and leads to permanent bone and joint damage.

Adamopoulos began investigating inflammation and arthritis at Oxford University, where he studied interactions of the immune and skeletal systems in the progression of the disease. His research currently focuses on cells known as osteoclasts and their role in triggering cellular and molecular events that lead to bone destruction.

Adamopoulos, an assistant professor in the UC Davis Department of Internal Medicine and researcher with the Northern California Institute for Pediatric Regenerative Medicine at Shriners Hospitals for Children – Northern California, will use the new funding to further define the effects of osteoclasts in the onset of arthritis and to identify therapeutics that block that process.

“We’ve made a lot of progress in arthritis treatment in the last decade, but there are still millions of patients who are not helped by those advances,” said Timothy Albertson, chair of the UC Davis Department of Internal Medicine. “Dr. Adamopoulos’ innovative thinking could reduce the pain and disability associated with arthritis and also has the potential to reduce the disease process.”

Adamopoulos was recruited to UC Davis in 2010 from the DNAX Research Institute, a division of Schering-Plough (currently Merck) in Palo Alto, where he discovered that the abnormal expression of a cytokine known as interleukin 23 (IL-23) activates osteoclast activity that causes severe arthritis and bone loss in mice. He has since confirmed that finding in human cells. His next step is to determine the potential of IL-23 inhibitors in arthritis treatment.

Adamopoulos was recognized in 2011 as an Arthritis National Research Foundation Scholar and Sontag Foundation Fellow, honors reserved for promising, early-career arthritis investigators. His findings were recently presented at the International Conference on Osteoimmunology in Corfu, Greece, and have been published in the Journal of Immunology, Journal of Experimental Medicine and Arthritis and Rheumatism. He serves as a reviewer for leading journals in rheumatology, as well as on the scientific advisory boards of biotechnology companies.

The new NIH funding (grant number R01-AR062173-01) will support Adamopoulos’ research for four years.

The National Institute of Arthritis and Musculoskeletal and Skin Diseases is one of the National Institutes of Health, the world’s largest source of funding for medical research. Based in Bethesda, Md., the agency is prepared to invest an estimated $225 million in arthritis research during 2012.

The UC Davis School of Medicine is among the nation’s leading medical schools, recognized for its research and primary-care programs. The school offers fully accredited master’s degree programs in public health and in informatics, and its combined M.D.-Ph.D. program is training the next generation of physician-scientists to conduct high-impact research and translate discoveries into better clinical care. Along with being a recognized leader in medical research, the school is committed to serving underserved communities and advancing rural health. For more information, visit medschool.ucdavis.edu.

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Novel PET/CT device shown to help monitor inflammatory arthritis

Custom-built device designed to improve upon existing imaging techniques.

High resolution PET/CT: image of the finger joints in a psoriatic arthritis patient; top - CT, bottom - PET, center - fusion of PET/CT.

UC Davis researchers have shown that their specially constructed PET/CT scanner enables better monitoring of the course of inflammatory arthritis — a costly and painful disease.

The custom-built device is designed to improve upon existing imaging techniques such as whole-body PET scans, which do not adequately reveal the effects of inflammatory arthritis such as rheumatoid and psoriatic arthritis in small joints.

Abhijit Chaudhari, assistant professor of radiology at UC Davis, presented his findings at a recent meeting of the Society of Nuclear Medicine and Molecular Imaging. The presentation was covered by AuntMinne.com, a leading radiology research news resource.

Inflammatory arthritis affects over 2 percent of the world’s population at a cost estimated at more than $40 billion, according to the AuntMinnie.com article. The disease can erode cartilage and bone and result in permanent disability.

Because the radiotracer used in PET scanning accumulates in areas of the body where inflammation occurs, Chaudhari and colleagues thought it might be a good marker for inflammatory arthritis.

For their study, Chaudhari tested four men and five women (five with rheumatoid arthritis and three with psoriatic arthritis). Each patient lay atop the scanning device gantry, with his or her hand or arm hanging down through a hole in the table. A PET/CT scanner rotated around the affected limb.

Radiological evaluations of the images found that classic symptoms associated with inflammatory arthritis were clearly identified from the PET scan on anatomical images captured from the CT.  They found that the uptake of the radiotracer correlated with findings on an MRI scan at areas in the limb where changes in the bone had occurred. Erosive changes in bone were better detected from the CT than from MRI scans. The findings suggest that PET/CT is useful both for disease monitoring as well as for determining whether a given treatment is working.

While there are new drugs effective in treating inflammatory arthritis, not every patient responds well to the treatment.

“Our initial studies with PET/CT show that it can separate responders form non-responders at an early time point, which is critical, because non-responders can try other drugs before their disease progresses, while responders can avoid the cost and toxicity associated with some of the more aggressive treatments,” Chaudhari said.

The system appeared to be sensitive to  early, albeit small changes in disease status, demonstrating that high resolution PET/CT is a potential tool for optimizing treatment and improving outcomes for inflammatory arthritis. In addition, PET/CT can produce detailed molecular and anatomical pictures of the status of disease, giving physicians and scientists new insights into the pathology responsible for inflammatory arthritis. One high-resolution picture from the device, for example, was chosen as the still image of the year by the American College of Rheumatology. The image showed the possible mechanism of inflammation of the nail bed that is typical in patients with psoriatic arthritis.

Chaudhari’s research and clinical trials using the device are being conducted with colleagues in the UC Davis departments of radiology, medicine and the Sacramento VA Medical Center. The multidisciplinary team consists of rheumatologists/scientists, clinical radiologists and physicians/biomedical engineers.

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Novel drug candidates offer new route to controlling inflammation

Initial tests show potential to treat diseases involving inflammation, such as asthma, stroke.

Dimitrios Morikis, UC Riverside

Pursuing a relatively untapped route for regulating the immune system, an international team of researchers has designed and conducted initial tests on molecules that have the potential to treat diseases involving inflammation, such as asthma, rheumatoid arthritis, stroke and sepsis.

The team, which included Dimitrios Morikis, professor of bioengineering at UC Riverside’s Bourns College of Engineering, started by creating a dynamic three-dimensional map of the structure of a protein called the C3a receptor, which sits on the surface of human cells and plays a critical role in regulating a branch of the immune system called the complement system.

They then used computational techniques to design short portions of protein molecules, known as peptides, that they predicted would interact with the receptor and either block or enhance aspects of its activity.

Finally, experimentalists validated the theoretical predictions by synthesizing the peptides and testing them in animal and human cells.

The researchers – a collaboration of teams at four institutions on three continents – published their results May 10 in the Journal of Medicinal Chemistry.

In addition to Morikis, the team included Christodoulos Floudas, the Stephen C. Macaleer ’63 Professor of Engineering and Applied Science in the Department of Chemical and Biological Engineering at Princeton University; Peter Monk of the Department of Infection and Immunity at the University of Sheffield Medical School, U.K.; and Trent Woodruff of the School of Biomedical Sciences at the University of Queensland, Australia.

The regulation of the complement system – so called because it complements the body’s central system of immune cells and antibodies – is thought to be a possible route to controlling over-active or mistaken immune responses that cause damage.

However, few drugs directly target complement proteins, and none targets the C3a receptor, in part because of the complexity of the complement system. In some cases complement activity can help downplay immune responses while in other cases it can stoke even stronger reactions.

The collaborators were able to create peptides that blocked activity of C3a (antagonists) and others that stimulated it (agonists) with unprecedented potency and precision.

Their success stems from a novel optimization-based approach, developed in the Floudas lab, for computing how a protein’s three-dimensional structure will change when changes are made in the protein’s chemical sequence. This ability to design peptides of a desired shape, allowed them to target the C3a receptor in precise ways.

Morikis and his graduate students Chris Kieslich and Li Zhang provided the collaborators 3-D structures, derived from molecular dynamics simulations, of the naturally occurring peptide that normally regulates the C3a receptor in human cells.

Using a portion of the structures as a flexible templates, Floudas and graduate students Meghan Bellows-Peterson and Ho Ki Fung designed new peptides that were predicted either to enhance or block C3a. Monk and postdoctoral fellow Kathryn Wareham tested the predictions in rat cells, while Woodruff and student Owen Hawksworth tested them in human cells. The Morikis group also performed physicochemical analysis of the structures that implicates electric fields generated by peptide charges as discriminating factors for agonist and antagonist activities.

Among the conditions potentially treatable through complement regulation is reperfusion injury, which occurs when blood flow is temporarily cut off to some part of the body, as in a heart attack or stroke, and then an inflammatory response develops when the blood returns.

Another possible use would be in organ transplantation, in which the body often mounts a destructive immune response against the newly introduced organ. Other common conditions affected by the complement system are rheumatoid arthritis and sepsis.

As next steps, the team will seek to test their peptides in live animal models of inflammation. They also plan to explore more generally the dual role of C3a in inflammation, with an eye toward developing further drug candidates.

The work was funded in part by the National Science Foundation, National Institutes of Health, University of California Tobacco-Related Disease Research Program, Beckman Initiative for Macular Research, US Environmental Protection Agency, British Heart Foundation, and the US Department of Defense.

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Migrating cells ‘turn right’

UCLA discovery has implications for engineering tissues, organs.

Diagonal pattern formed by migrating cells

What if we could engineer a liver or kidney from a patient’s own stem cells? How about helping regenerate tissue damaged by diseases such as osteoporosis and arthritis? A new UCLA study bring scientists a little closer to these possibilities by providing a better understanding how tissue is formed and organized in the body.

A UCLA research team discovered that migrating cells prefer to turn right when encountering changes in their environment. The researchers were then able to translate what was happening in the cells to recreate this left–right asymmetry on a tissue level. Such asymmetry is important in creating differences between the right and left sides of structures like the brain and the hand.

The research, a collaboration between the David Geffen School of Medicine at UCLA and the Center for Cell Control at UCLA’s Henry Samueli School of Engineering and Applied Science, appears in today’s (Feb. 17) issue of the journal Circulation Research.

“Our findings suggest a mechanism and design principle for the engineering of tissue,” said senior author Dr. Linda L. Demer, a professor of medicine, physiology and bioengineering and executive vice chair of the department of medicine at the Geffen School of Medicine. “Tissue and organs are not simply collections of cells but require careful architecture and design to function normally. Our findings help explain how cells can distinguish and develop highly specific left–right asymmetry, which is an important foundation in tissue and organ creation.”

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Motion promotion

UC Irvine center explores, extols health benefits of exercise in childhood.

Dan Cooper, UC Irvine

Dr. Dan Cooper believes that exercise can be the best medicine — so much so that he’s studying how specifically designed exercise programs for at-risk kids can help curb excessive weight gain, fight diseases and foster long-term fitness.

With childhood obesity and asthma emerging as national health crises, Cooper in 2006 founded UC Irvine’s Pediatric Exercise Research Center, and over the past six years, it has shed light on the full benefits of physical activity.

At any one time, PERC hosts 15 to 20 studies of how — and how much — exercise works to avert type 2 diabetes, limit asthma attacks, thwart arthritis, prevent cancer, encourage mineralization in growing bones, and improve the quality of life for kids with chronic diseases and congenital disorders.

“Our purpose is to recognize the importance of exercise for health and growth in children,” says Cooper, professor and chair of pediatrics at UCI and director of the Institute for Clinical & Translational Science, which supports PERC efforts. “We’re one of the few centers in the country to focus on this crucial issue.”

He and PERC’s associate director, gymnast Shlomit Aizik, maintain that exercise is necessary not only for good childhood health but also to prevent later-in-life maladies such as heart disease and stroke.

Cooper was one of the principal investigators for the nationwide Healthy study, which involved healthier cafeteria choices, longer and more intense periods of physical activity, and robust in-school education programs to lower rates of obesity and other risk factors for type 2 diabetes.

Besides its role in overall fitness, exercise also triggers biochemical mechanisms that activate anti-inflammatory cells and important growth factors, Aizik says.

PERC-supported research on these biochemical mechanisms opened the door to understanding the positive influence of physical activity on immune diseases — most commonly asthma and, to a lesser extent, arthritis, which is increasingly seen in obese children — while addressing a pressing question.

“How much exercise is too much?” Cooper says. “Too much can actually worsen these conditions. The challenge is determining the right ‘dose’ of exercise to achieve anti-inflammatory benefits without causing future harm. PE teachers are not trained for this, so we’re establishing programs to help schools properly integrate the correct amount of exercise.”

PERC researchers are also probing the impact of physical activity during key stages of child development. For example, studies show that diet and exercise are linked to proper mineralization in growing bones, which can stave off osteoporosis in middle and old age.

A PERC group is currently looking at the effects of exercise on infants born two to three months early, missing out on a phase of fetal life marked by lots of body-conditioning physical movement. “This is lost when babies are born prematurely, interfering with a critical growth period,” Cooper says.

His team has created an activity program to offset this deficit. It starts, he says, with passive manipulation of a newborn’s arms and legs and progresses over 12 months to include such motions as head lifting and crawling. After a year, researchers will assess the influence of the exercise on body composition, bone mineralization and additional developmental markers.

Another PERC effort — led by Aizik — seeks to increase physical activity among kids with congenital conditions. College students are being trained to engage spina bifida patients at Miller Children’s Hospital Long Beach in exercise.

“Youngsters with disabilities rarely get enough physical activity,” Aizik says. “And studies show that it improves and extends the quality of life for these children. We want to measure the psychological and physiological results of this mentor-based program to see how we can incorporate an appropriate amount of exercise into their lives.”

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