The Journal Of Clinical Investigation Online Early Table Of Contents: April 15, 2008

Clearer day for gene therapy: new vector carries big genes linked to inherited blindness

Some clinicians and researchers hope that individuals with inherited diseases (such as cystic fibrosis and recessive Stargardt disease, which causes progressive loss of sight) might one day be cured by providing them with a corrected version of their disease-causing faulty gene, i.e., by gene therapy. In gene therapy, the curative gene is packaged in an agent known as a vector, which carries the gene into cells where it is required. One of the most common vectors is derived from a virus, adeno-associated virus (AAV). However, for some diseases, such as recessive Stargardt disease, one barrier to successful gene therapy is that AAV is not able to accommodate the large size of the curative gene. New data, generated by Alberto Auricchio and colleagues, at the Telethon Institute of Genetics and Medicine, Italy, has revealed that vectors derived from a specific form of AAV known as AAV5 can accommodate large genes, including that missing in a mouse model of recessive Stargardt disease.

In the study, it was found that much larger genes could be packaged into vectors derived from AAV5 than from vectors derived from other forms of AAV. Further, it was shown that AAV5 could be used to induce cells to successfully convert the information in the large genes into protein. When AAV5 containing the mouse gene Abca4, which is the mouse correlate of the gene mutated in individuals with recessive Stargardt disease, was injected into the eye of mice lacking Abca4, improvement in the function of the eye was observed. The authors therefore concluded that vectors derived from AAV5 could be useful for treating individuals with recessive Stargardt disease.

TITLE: Serotype-dependent packaging of large genes in adeno-associated viral vectors results in effective gene delivery in mice

AUTHOR CONTACT:

Alberto Auricchio
Telethon Institute of Genetics and Medicine, Naples, Italy.

Walking on AIRE: how the G228W AIRE mutation causes disease

Individuals develop the autoimmune disease autoimmune polyglandular syndrome type 1 (APS1) if both copies of their AIRE gene are mutated such that they make no functional AIRE protein. APS1 is characterized by a specific group of symptoms, and many different mutations in the AIRE gene have been linked to this disease. Recently, individuals with a mutation known as G228W in just one copy of their AIRE gene have been identified and shown to exhibit a different pattern of symptoms to individuals with APS1. Insights into the mechanisms by which the G228W mutation causes autoimmunity have now been provided by Mark Anderson and colleagues, at the University of California, at San Francisco, Diabetes Center.

In the study, mice were engineered such that they expressed the G228W mutation. These mice were found to have a defect in a process known as negative selection, which is the process by which immune cells known as T cells that target our own organs are eliminated, such that T cells able to target the organs of the mouse escaped and caused autoimmunity. This defect occurred because the G228W mutant AIRE bound normal AIRE and sequestered it in nuclear inclusion bodies so that it could not carry out its function. As the G228W mutant AIRE was unable to prevent all normal AIRE from functioning, these data indicate that even low levels of AIRE function are insufficient to prevent autoimmunity.

TITLE: Mechanisms of an autoimmunity syndrome in mice caused by a dominant mutation in Aire

AUTHOR CONTACT:

Mark S. Anderson
University of California at San Francisco Diabetes Center, San Francisco, California, USA.

The protein KIM-1 enables kidney cells to clear up the mess made by dead cells

The clearance of dead cells is a necessary part of tissue repair after injury and scavenger cells known as macrophages have a central role in this process. However, it has been suggested that epithelial cells at the site of an injury can also perform this task, and evidence that epithelial cells in the kidney can do so has now been provided by a group of researchers at Brigham and Women’s Hospital, Boston.

The protein KIM-1 (also known as TIM-1) is upregulated on the surface of injured kidney epithelial cells. In the study, it was found that upregulation of KIM-1 enabled rat, pig, and dog kidney epithelial cells to take up cells that had died by a process known as apoptosis. The uptake of the apoptotic cells, by a process known as phagocytosis, occurred after KIM-1 bound molecules on the surface of the apoptotic cells, specifically phosphatidylserine and oxidized lipoproteins. These data suggest a role for KIM-1 in repair of the lining of the kidney tubules following injury.

TITLE: Kidney injury molecule-1 is a phosphatidylserine receptor that confers a phagocytic phenotype on epithelial cells

AUTHOR CONTACT:

Takaharu Ichimura
Brigham and Women’s Hospital, Harvard Institute of Medicine, Boston, Massachusetts, USA.

Jeremy S. Duffield
Brigham and Women’s Hospital, Harvard Institute of Medicine, Boston, Massachusetts, USA.

ROCK solid: A key role for the protein ROCK1 in vessel wall damage

Diseases that affect the heart and/or blood vessels are known as cardiovascular diseases and they include high blood pressure (also known as hypertension), stroke, and atherosclerosis. The disease-causing changes to blood vessels in some cardiovascular diseases occur as a result of a damaging inflammatory response to blood vessel injury, and increased activity of members of the ROCK family of proteins has been linked to this process. However, several cell types are involved in the blood vessel-damaging inflammatory response to injury and it has not been determined which specific ROCK protein is involved in which specific cell type. In a new study, using mice expressing only one of the genes containing the information for making ROCK1 (Rock1+/- mice) and mice expressing only one of the genes containing the information for making ROCK2 (Rock2+/- mice), James Liao and colleagues at Brigham and Women’s Hospital and Harvard Medical School, Boston, have shown that ROCK1, and not ROCK2, mediates damaging changes to blood vessels after they have been injured by being closed off. The lack of damaging changes to blood vessels in Rock1+/- mice was associated with decreased inflammatory cell mobilization to the site of injury. Further analysis indicated that ROCK1 expression in bone marrow-derived cells, most probably inflammatory cells, was important for mediating the damaging changes to blood vessels after injury. The authors therefore concluded that ROCK1 might provide a useful target for treating inflammatory diseases of blood vessels.

TITLE: ROCK1 mediates leukocyte recruitment and neointima formation following vascular injury

AUTHOR CONTACT:

James K. Liao
Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA.

‘Til death do us part: death of nerves in the gut causes intestinal disease

The nerves that control the gut form part of a network known as the enteric nervous system. Dysfunction in this system can lead to intestinal diseases such as Hirschsprung disease (also known as congenital intestinal aganglionosis), which occurs when part of the enteric nervous system is missing, meaning that the gut cannot function properly, leading to intestinal blockages and inflammation. Hirschsprung disease occurs most commonly in children born with mutations in their RET gene, but the reasons for this link have not been determined. In a new study, Hideki Enomoto and colleagues at the RIKEN Center for Developmental Biology in Kobe, Japan, have demonstrated that mice with reduced expression of the Ret gene show features of Hirschsprung disease. Disease was associated with impaired migration of precursors of enteric nerves to the gut and decreased survival of these precursor cells. If expression of the Ret gene was reduced after precursors of enteric nerves had migrated to the gut and developed into nerves, the enteric nerves that had already developed did not survive. Thus, the authors suggest that decreased Ret expression impairs the survival of both precursors of enteric nerves and enteric nerves themselves and that this cell death is potentially involved in the etiology of Hirschsprung disease.

TITLE: Diminished Ret expression compromises neuronal survival in the colon and causes intestinal aganglionosis in mice

AUTHOR CONTACT:

Hideki Enomoto
RIKEN Center for Developmental Biology, Kobe, Japan.

Source: Karen Honey

Journal of Clinical Investigation

MCV Foundation To Receive $500,000 Research Donation

A new partnership between Richmond Eye & Ear Healthcare Alliance (REEHA) and the Medical College of Virginia Foundation will provide over $500,000 for the VCU Health System’s Department of Orthopaedics through December 2014. The multi-year research donation, called the Richmond Eye and Ear Healthcare Alliance Research and Education Fund, demonstrates the Alliance’s continuing commitment to the leading research and education facilities in Virginia to be at the forefront of medical advancement and care.

“This is an incredibly exciting new partnership between the REEHA and the [MCV] Foundation,” said Robert S. Adelaar, MD, Chairman, Department of Orthopaedics, VCU Health System. “The donation from Richmond Eye & Ear Healthcare Alliance will provide instrumental support for the Department’s research and education goals.”

“The Richmond Eye & Ear Healthcare Alliance is always looking for ways to support medical research and education,” said Bruce Kupper, REEHA President/CEO and CEO of REEHA affiliate Stony Point Surgery Center. “This gift will enable VCU Health System’s Department of Orthopaedics to fund various education and research projects for faculty, staff and students, as our two organizations continually strive to advance Richmond as a leader in the medical industry. The VCU Department of Orthopaedics has long been a leader in the Richmond area, as well as at the national level, for the quality of its residency program, research and clinical care. REEHA is proud to be a part of this partnership and excited about its potential.”

According to the November agreement, Richmond Eye & Ear Healthcare Alliance will provide the Medical College of Virginia Foundation with $100,000 each December through 2014, totaling $500,000 over the five years. Other scientific funding provided to VCU since 2002 from REEHA and the Richmond Eye & Ear Foundation totals more than $300,000. The two organizations have also funded medical research for the University of Virginia Health System, Eastern Virginia Medical School and Ohio State University, totaling over $300,000.

Dr. Adelaar, along with VCU Health Sciences Vice President and VCU Health System CEO Sheldon M. Retchin, MD, MSPH, School of Medicine Dean Jerome F. Strauss III, MD, PhD, and MCV Foundation President William P. Kotti, PhD will receive the gift from REEHA President/CEO Bruce Kupper.

Source: Richmond Eye & Ear Healthcare Alliance

OpenEye Launches The ‘SAMPL’ Blind Challenge

OpenEye Scientific Software, Inc., developer of innovative molecular modeling and cheminformatics solutions for drug discovery, announced the launch of the first edition of the Statistical Assessment of the Modeling of Proteins and Ligands (SAMPL-1) blind challenge.

SAMPL is a blind test of protein and ligand modeling; an analysis of methods on data not seen by participants. “With SAMPL we intend to avoid ‘who won, who lost’,” explained Dr. Anthony Nicholls, President and CEO of OpenEye Scientific Software. “Rather, we see this as an opportunity for groups to test their methods, learn from the experience and share lessons learned.” In addition, third party testers, particularly professional modelers, are encouraged to participate so as to allow comparisons of single methods when used by several, independent, participants.

SAMPL-1 will consist of two sets of protein-ligand binding data, generously provided by Abbott Labs and Vertex Pharmaceuticals, and sixty-three vacuum-water transfer energies, courtesy of Peter Guthrie at the University of Western Ontario, and Chemical Computing Group. The two sets of protein-ligand data each have between twenty and seventy active compounds, the majority with protein-ligand crystal structures. The assessment will consist of three parts:

1. Virtual Screening.
2. Predicting binding poses.
3. Predicting binding affinities.

“Hopefully SAMPL will prove useful and become a regular event. There are many possible variants we could try in future assessments, such as providing partial information, e.g. a subset of actives or binding modes, more typical of an industrial project setting. Additional physical properties, such as tautomer ratios, pKas, and thermodynamic data could be sought. I strongly believe a prospective component to our field will help us judge progress and I hope many modelers both agree and contribute,” concluded Dr. Nicholls.

The results of SAMPL-1 will be presented at the CUP IX meeting, March 17th-19th in Santa Fe. All participants will be offered a speaking slot at the meeting. The deadline for submission of results is on February 18th, 2008, one month before the CUP IX meeting. For more details, please see sampl.eyesopen/.

About OpenEye

OpenEye Scientific Software Inc. is a privately held company headquartered in Santa Fe, New Mexico, with offices in Boston, Massachusetts and Strasbourg, France. It was founded in 1997 to develop large-scale modeling applications and toolkits. Primarily aimed towards drug discovery and design, areas of application include chemical informatics, structure generation, docking, shape comparison, charge & electrostatics and visualization. The software is designed for scientific rigor, as well as speed, scalability and platform independence. OpenEye makes most of its technology available as toolkits – programming libraries suitable for custom development. OpenEye software typically is distributable across multiple processors, supports 64-bit processing, and runs on Linux, Windows and Mac OS X, as well as HP, IBM, SGI and SUN flavors of UNIX.

eyesopen

News From The Journal Of Neuroscience

1. Polyhedral Cages Dock Vesicles at Active Zones
Guido A. Zampighi, Nick Fain, Lorenzo M. Zampighi, Francesca Cantele, Salvatore Lanzavecchia, and Ernest M. Wright

When looking at schematic illustrations of proteins found in presynaptic active zones, it is hard to imagine how all those proteins fit together in the cell. Even with electron microscopy, the organization of vesicle docking machinery is difficult to discriminate. But this week, Zampighi et al. present images of active zone complexes that were visualized using conical electron tomography. The authors used semiautomated volume-rendering techniques that colored individual voxels based on density thresholds and/or topology. The resulting images revealed that active zones of rat cortical synapses contain several units, each of which comprised a central polyhedral cage (which the authors call a syndesome) surrounded by synaptic vesicles. Some of these vesicles were partly or fully fused to the plasma membrane, suggesting that the polyhedral cages help mediate vesicle docking and fusion. Interestingly, the polyhedral cages resemble those of clathrin coats, which are normally associated with endocytosis rather than exocytosis.

2. Neurturin and Ret Influence Retinal Circuit Formation
Milam A. Brantley Jr, Sanjay Jain, Emily E. Barr, Eugene M. Johnson Jr, and Jeffrey Milbrandt

The receptor tyrosine kinase Ret, which is activated by glial-cell-line-derived neurotrophic factor (GDNF) family ligands (GFLs), is essential for development of many tissues, and GDNF can slow retinal degeneration in animal models. Brantley et al. have detailed the role of this signaling pathway in retinal development. Mice with reduced Ret expression showed decreased light responses, as did mice lacking the GFL neurturin, but not other GFLs. Expression of fluorescent reporters under the control of Ret or neurturin receptor promoters indicated that both of these molecules are expressed in horizontal cells and some amacrine and ganglion cells. In neurturin knock-out mice, the outer plexiform layer (where photoreceptors synapse with horizontal and bipolar cells) was disorganized, horizontal cell axons and dendrites were sparse, bipolar and horizontal cell processes were abnormally long, and synapses were mislocalized to the outer nuclear layer. Therefore, neurturin-mediated Ret signaling appears necessary for normal circuit development in the retina.

3. Disinhibition Drives OFF Cell Depolarization
Michael B. Manookin, Deborah Langrill Beaudoin, Zachary Raymond Ernst, Leigh J. Flagel, and Jonathan B. Demb

It has been assumed that depolarization of retinal ganglion cells is driven by excitation from bipolar cells. Manookin et al. now report that OFF ganglion cells are also driven by reduced inhibition. Responses to light increments and decrements were recorded in guinea pig ON and OFF ganglion cells. At all increment levels, ON cells received both excitatory and inhibitory inputs; but at each decrement level, increased excitation of OFF cells was paired with decreased inhibition. By sequentially applying receptor agonists and antagonists to test each type of synapse (including gap junctions), it was determined that OFF cell inhibition is mediated by AII amacrine cells, which are electrically coupled to ON cone bipolar cells. When the light dims, ON cone bipolar cells hyperpolarize, which hyperpolarizes AII amacrine cells, thus reducing their inhibition of OFF ganglion cells. This disinhibition is the dominant driving force for OFF ganglion cells when light decrements are small.

4. Microglia Delimit Alzheimer Plaques
Tristan Bolmont, Florent Haiss, Daniel Eicke, Rebecca Radde, Chester A. Mathis, William E. Klunk, Shinichi Kohsaka, Mathias Jucker, and Michael E. Calhoun

Microglia play roles in many neurological diseases, including Alzheimer’s disease (AD). In AD, microglia surround amyloid plaques, but it is not clear whether they are harmful (e.g., promoting inflammation) or beneficial (e.g., restricting plaque growth). To gain some insight into their function, Bolmont et al. imaged interactions occurring in vivo between microglia and amyloid plaques in a mouse model of AD. Microglia extended and retracted processes in all directions, but those that were near plaques extended more processes toward the plaque. Many nearby microglia migrated to the edge of a given plaque and remained there, but there was an upper limit to the number of microglia surrounding any plaque: larger plaques were associated with larger, not more, microglia. The total volume of microglia surrounding a plaque was predictive of whether the plaque grew over time, and microglia appeared to take up amyloid particles, suggesting the microglia may limit plaque growth.

Please click here for the current table of contents.

Source: Sara Harris

Society for Neuroscience

Broad New TAU Study Finds Statins Cut Cataract Risk

Statins, a class of drugs used to lower cholesterol levels, have been successfully fighting heart disease for years. A new study from Tel Aviv University has now found that the same drugs cut the risks of cataracts in men by almost 40%.

“Doctors have known for some time that there is some sort of preventative effect that statins have against cataracts,” says Dr. Gabriel Chodick of the Department of Epidemiology and Preventive Medicine at the Sackler Faculty of Medicine at Tel Aviv University, who led the study. “It seems that they protect the eye from inflammation and ocular nerve cells from a process of oxidization. But ours is the first study to show such a strong association in such a large population.”

The study covered over 180,000 patients between the years of 1998 and 2007 and was published in the February 2010 issue of the Annals of Epidemiology.

From the heart to the head

Dr. Chodick and his colleague Dr. Varda Shalev found that men aged 45 to 54 who took the statins daily to lower their cholesterol levels also lowered their chances of developing cataracts by 38%. For women of about the same age, the risk for cataracts was also cut dramatically, by about 18%.

Dr. Chodick has been studying the health benefits of statins for years. One of his recent studies, featured as part of a Time magazine cover story, showed that statins can reduce a person’s chance of dying from all combined diseases and conditions by 40% – something in the medical community called “all-cause mortality.”

“People who persistently take statins have tremendously reduced chances of premature death by disease. We began to think that statins, which are proven to prevent cardiovascular disease, may do other good things in the body as well. We started investigating cataracts to show statins’ effects in a more statistical manner,” says Dr. Chodick.

A statin a day ??¦

“Statins are not being taken consistently by patients, and only about 10% of those who get these prescriptions actually end up taking them. Once you start, it’s important to continue taking them to avoid cardiovascular problems,” Dr. Chodick warns. “But now we have even more good reasons to keep taking statins – like an apple a day. People who begin taking them in their 40s to early 60s can reap a number of benefits, including better protection against cataracts.”

A cataract is a type of clouding that develops in the lens of the eye, leading to varying degrees of sight impairment. It typically progresses slowly so that the sufferer may not even be aware of the problem. If left untreated, a cataract can lead to blindness. In the U.S., cataracts affect about 60% of both men and women over the age of 60. About 1.5 million cataract surgeries are performed in the U.S. each year, and visual disabilities associated with cataracts lead to over 8 million physician office visits a year.

“We believe that the regular use of statins for men and women under the age of 75 can significantly protect them against cataracts,” Dr. Chodick concludes. Whether people who are not at risk for heart attacks should take them as a cataract preventative alone has not been determined. But before long we may be taking a daily statin pill along with our daily vitamin tablet, Dr. Chodick believes.

Source:
George Hunka
American Friends of Tel Aviv University

New Insights Into Vision Loss, Australia

A trigger for the most common form of vision loss and blindness in Australia has been discovered thanks to research conducted with help from Australian eye donors.

Researchers from the United States, United Kingdom and Australia, including The Australian National University’s Vision Centre, found that patients suffering from the most common form of age-related macular degeneration (AMD) lack a critical enzyme – DICER-1. The findings were published in today’s issue of the journal Nature.

AMD affects one in every seven Australians over 70 and is a leading cause of blindness among the elderly. Patients suffering the disease experience difficulties reading or recognising faces. The research findings could lead to new treatments for this previously untreatable disease.

Professor Jan Provis from the ANU Vision Centre said the research found that the enzyme, DICER-1, is reduced in the eyes of those suffering the ‘dry’ form of AMD, causing changes in cells that lead to the premature death of the vision cells.

“We’ve known for some time that cell death is the cause of ‘dry’ AMD. What was not clear until now was which mechanism caused the cells to die,” said Professor Provis.

“This discovery relied on the help of Australians who donated their eyes through the Lions NSW Eye Bank.

“Thanks to these donations, we were able to collect critical evidence to confirm that a deficit of DICER-1 was causing the cells to die,” she said.

Professor Provis said that understanding what causes the cell death takes scientists a step closer to finding a possible treatment for this form of AMD. The discovery identifies a new role for DICER-1 which is also implicated in some forms of cancer.

“Dry macular degeneration affects very large numbers of elderly Australians, and is presently untreatable. The existing forms of AMD therapy, that involve injections into the eye, are not appropriate for this ‘dry’ form of the disease. The research not only shows that DICER-1 is reduced, but also identifies the regulator that is responsible for its reduction. That is where new therapies can be targeted,” said Professor Provis.

Jan Provis is Professor of Anatomy in the ANU Medical School, and Associate Director of the Vision Centre. The Vision Centre is funded by the Australian Research Council as the ARC Centre of Excellence in Vision Science.

The paper, ‘DICER1 deficit induces Alu RNA toxicity in age-related macular degeneration’, is published in the current issue of Nature.

Source:

Australian National University

Gene Responsible For Blindness In Infants And Children Identified By MUHC-Led International Team

A MUHC-led study identifies a gene responsible for Leber Congenital Amaurosis (LCA), the most common cause of congenital blindness in infants and small children. The study, partly funded by the Foundation Fighting Blindness in Canada (FFB-C), is published in Nature Genetics.

“This discovery has the potential to fast-track a cure for this disease,” says lead investigator Dr. Robert Koenekoop, director of the McGill Ocular Genetics Centre at the MUHC. “Our main research goal is to identify all the genes responsible for congenital blindness in children and then study them so that we can then use gene therapy to rescue their vision.”

Working with an international team of researchers including Drs. Anneke den Hollander, Frans Cremers and Ronald Roepman from the University of Nijmegen in The Netherlands, and Dr. Chris Inglehearn from The University of Leeds in the UK, Dr. Koenekoop and his team, including Dr. Irma Lopez, used a new technique called SNP (single nucleotide polymorphism) technology to identify homozygous regions in the genome, which led to the discovery of the new gene called LCA5. In the past, large families were necessary to find genes, but in this study only samples from one Quebec and one American patient were used to accomplish this. The SNP micro array technology accelerated the process of locating the gene and enabled the investigators to isolate it within a few months instead of several years. “This method may become a model for identifying other retinal diseases and causes of blindness in the future,” says Dr. Koenekoop, who is also associate professor in Ophthalmology and Human Genetics at McGill University.

The same international research team identified the CEP290 gene last year, the most common genetic cause of LCA (American Journal of Human Genetics September, 2006). By using the protein structure of CEP290, the investigators were able to discover LCA5, as they have similar structures and functions in the retina. Both the CEP290 and LCA5 genes encode proteins with vital functions in the cilium of the photoreceptors, transporting visual proteins to the compartment where vision occurs. When these genes are mutated, which occurs in about 25 to 30 per cent of blind children, the visual proteins are not transported properly to the outer segments, causing the photoreceptors to stop working and die.

This year, after many years of research on a related LCA gene called RPE65 and a spectacular rescue of vision by RPE65 gene replacement in dogs with LCA, human clinical trials have started in London, UK and in Philadelphia, USA. “Preliminary results have been very encouraging and we expect to launch clinical trials investigating gene replacement for CEP290 and LCA5 in the near future,” says Dr. Koenekoop.

An estimated 200,000 children worldwide are afflicted with LCA.

The FRSQ, the TD FINANCIAL GROUP and The Foundation Fighting Blindness in Canada (FFB-C) funded this research. “Discoveries like this one show us that treatments and cures are in sight. The Foundation Fighting Blindness in Canada is proud to fund quality vision research at the MUCH that is giving hope to families affected by blindness,” says Sharon Colle, National Executive Director of the FFB-C.

Contact:
Alex Fretier

About the McGill University Health Centre

The McGill University Health Centre (MUHC) is a comprehensive academic health institution with an international reputation for excellence in clinical programs, research and teaching. The MUHC is a merger of five teaching hospitals affiliated with the Faculty of Medicine at McGill University – the Montreal Children’s, Montreal General, Royal Victoria, and Montreal Neurological hospitals, as well as the Montreal Chest Institute. Building on the tradition of medical leadership of the founding hospitals, the goal of the MUHC is to provide patient care based on the most advanced knowledge in the health care field, and to contribute to the development of new knowledge.

The Research Institute of the McGill University Health Centre (RI MUHC) is a world-renowned biomedical and health-care hospital research centre. Located in Montreal, Quebec, the institute is the research arm of the MUHC, a university health center affiliated with the Faculty of Medicine at McGill University. The institute supports over 500 researchers, nearly 1000 graduate and post-doctoral students and operates more than 300 laboratories devoted to a broad spectrum of fundamental and clinical research. The Research Institute operates at the forefront of knowledge, innovation and technology and is inextricably linked to the clinical programs of the MUHC, ensuring that patients benefit directly from the latest research-based knowledge. For further details visit: muhc/research.

Contact: Alex Fretier

McGill University Health Centre

Optometrists: Got The Flu? Take Out Your Contacts

Whether it’s the low temperature and humidity facilitating the spread of viruses, or the fact that people spend more time cooped up together indoors, winter is the season for colds and flu. Experts at the University of Alabama at Birmingham (UAB) School of Optometry advise those who catch a virus to avoid wearing contact lenses.

“Many people don’t realize that their eyes function differently when they’re sick,” said William “Joe” Benjamin, Ph.D., professor of optometry at UAB. “Tear production is altered, and eyes tend to get very dry. People may develop pink eye, conjunctivitis or other eye infections. The cornea can swell. Contacts can aggravate these symptoms.”

Benjamin says people who are sick should stick to glasses. For those who must wear contacts, they should make sure to clean them thoroughly or, if possible, switch to daily wear lenses to avoid infection. Even taking contacts out to let eyes recuperate during the day can be beneficial.

University of Alabama at Birmingham
701 20th St. S., AB 1320
Birmingham, AL 35294-0113
United States
main.uab.edu

Association for Research in Vision and Ophthalmology

The Association for Research in Vision and Ophthalmology (ARVO) announced today that Joan W. Miller, MD, and Joel S. Schuman, MD, have been selected to receive the 2006 ARVO/Pfizer Ophthalmics Translational Research Award during ARVO’s Annual Meeting to be held in Fort Lauderdale, Fla., in May 2006.

The ARVO/Pfizer Award is presented to honor excellence in research and fundamental scientific discoveries, concepts and novel technologies, leading to clinical evidence of diagnosis, prevention, or amelioration of the pathological eye and/or an understanding of the normal vision processes. The award is presented to two researchers annually.

Miller was selected for her research in non-human primates, and subsequent translation to humans, leading to the development of photodynamic therapy of neovascular age-related macular degeneration. She is the Henry Willard Williams Professor and Chair of Ophthalmology at Harvard Medical School. In addition, Miller is Chief of Ophthalmology at the Massachusetts Eye and Ear Infirmary in Boston. She is a past recipient of the American Academy of Ophthalmology Achievement Award, the Alcon Research Institute Award, and the Retina Research Award of the Club Jules Gonin. Miller is the Chairman of the Executive Committee of the Harvard Medical School Department of Ophthalmology.

Schuman was chosen for his role as a key researcher in the development of optical coherence tomography that is widely used clinically in the diagnosis and management of glaucoma and retinal diseases. He is Eye and Ear Foundation Professor and Chairman of Ophthalmology at the University of Pittsburgh School of Medicine. In 2002, Schuman received the Alcon Research Institute Award of Excellence and, the following year, the American Academy of Ophthalmology’s Senior Achievement Award. He serves on numerous editorial boards for vision-related journals including Investigative Ophthalmology & Visual Science and Glaucoma Today, and is also a member of the Executive Committee of the University of Pittsburgh School of Medicine.

Established in 1928, ARVO is a membership organization of more than 11,300 eye and vision researchers from over 70 countries. The Association encourages and assists its members and others in research, training, publication, and dissemination of knowledge in vision and ophthalmology. ARVO’s headquarters are located in Rockville, Md. For more information about ARVO, logon to the Association’s Web site, arvo

Elinore Tibbetts
etibbettsarvo
arvo

View drug information on Photodynamic Therapy.

Light-sensing Cells In Retina Develop Before Vision

Investigators at Washington University School of Medicine in St. Louis have found that cells making up a non-visual system in the eye are in place and functioning long before the rods and cones that process light into vision. The discovery should help scientists learn more about the eye’s non-visual functions such as the synchronization of the body’s internal, circadian clock, the pupil’s responses to light and light-regulated release of hormones.

The researchers report in the Dec. 22 issue of Neuron that in the mouse retina, intrinsically photosensitive retinal ganglion cells (ipRGCs) are active and functioning at birth. That was surprising because the mouse retina doesn’t develop fully until a mouse is almost three weeks old, and the first rod cells don’t appear until about 10 days after birth.

“We were stunned to find these photoreceptors were firing action potentials on the day of birth,” says Russell N. Van Gelder, M.D., Ph.D., associate professor of ophthalmology and visual sciences and of molecular biology and pharmacology. “Mice are very immature when they’re born. It takes about three weeks after birth for the retina to fully develop. No one previously had detected light-dependent cell firing in a mouse before 10 days.”

Van Gelder says the ganglion cells react to light in two ways, sending messages to parts of the brain that control circadian rhythms, and (on the first day or two of life) also setting off a wave of activity that spreads through the retina, possibly helping visual cells develop.

Van Gelder and colleagues have spent the last few years learning how blind animals (and people) can sense light and use it to set their circadian clocks. The ipRGCs were first identified in 2002 — by David M. Berson, Ph.D., and colleagues at Brown University — as the cells that could sense light even in visually blind eyes. But it was very difficult and time consuming to isolate and study the cells, requiring precise injection of a tracing dye into the brains of animals to label and identify the ipRGCs.

That has changed as the result of a technical advance developed by Daniel C. Tu and Donald Zhang, both Medical Scientist Training Program students in Van Gelder’s lab, and co-first authors of this study. Tu and Zhang used a multi-electrode array technique in which tiny, individual electrodes are placed about 200 microns apart. Each electrode is a mere 30 microns in size — there are 25,400 microns per inch –and 60 electrodes are contained on a grid.

“This spacing turns out to be perfect for a retina,” Van Gelder says. “You can remove the retina and place it, ganglion cell-side down, on this array. Then the electrodes pick up the impulses of the ganglion cells when those cells react to light.”

Whereas the original brain injection technique allowed researchers to study only one or two ipRGCs per day, the multi-electrode array allows Van Gelder’s team to study 30 times that many. Those studies have revealed a cell population that reacts quickly and consistently to light.

“If you give the cells a series of identical pulses of light and look at how fast they fire, the reaction is identical every time,” Van Gelder says. “The ganglion cells detect brightness, and they’re extremely good at it. You could make a good light meter for a camera out of these cells because they are consistent in their response to brightness over the equivalent of almost 10 f-stops on a camera. That’s completely different from the rods and cones in the retina. Those visual cells can’t detect brightness very well. They detect contrast, sensitivity and motion.”

Studying these populations of ipRGCs, Van Gelder also found the cells require a protein called melanopsin to sense and react to pulses of light. When the group examined retinas of mice that were genetically engineered to lack melanopsin, they found that the ganglion cells lost all sensitivity to light.

The ability to study many of these cells at once allowed Van Gelder’s team to learn that there are three distinct populations of ipRGCs, and each cell type reacts to light differently. Some fire quickly when a light turns on but take longer to stop firing when it goes out. Other cells take a while to ramp up their response but then quickly stop firing when the area gets dark. A third cell type is slow to turn on when exposed to light and takes its time shutting down in darkness.

In addition, the cells tend to react to light in groups. Electrically, some of the cells work almost like a chorus, sending several synchronized “harmonies” to the brain as part of one big “song” that responds to light impulses.

“We were able to detect about 20 percent of the ganglion cells were coupled to other ganglion cells,” he says. “That’s probably a low estimate because if we had a finer grid and could record the activities of more individual cells, we might well find more interactions.”

Van Gelder believes the early activity and the interactions of the ipRGCs may somehow enhance survival by helping animals detect light and set their circadian clocks prior to the development of vision. And he says because retinas tend to be very similar in most mammals, human ganglion cells also may develop and begin to function earlier than rods and cones.

Although ipRGCs sense light in mice and humans, they don’t connect to the brain’s visual cortex. Instead, they send signals to deeper, more ancient parts of the brain, such as the hypothalamus, from which they project to the brain regions that control the circadian clock as well as the response of the pupil to light.

“The multi-electrode array technique that Dan Tu and Don Zhang have brought into this field should help us learn a lot more about how these retinal ganglion cells influence all kinds of non-visual functions and reinforce the fact that the eye is responsible for more than just vision,” Van Gelder says.

Tu DC, Zhang D, Demas J, Slutsky EB, Provencio I, Holy TE, Van Gelder RN. Physiologic diversity and development of intrinsically photosensitive retinal ganglion cells. Neuron, vol. 48:6, Dec. 22, 2005.

This research was supported by the National Eye Institute of the National Institutes of Health and by the Medical Scientist Training Program of Washington University School of Medicine. Additional support was provided by the Culpepper Physician-Scientist Award of the Rockefeller Brothers Foundation and by a grant from the McDonnell Foundation for Systems Neuroscience.

Washington University School of Medicine’s full-time and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked third in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

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Jim Dryden
jdrydenwustl.edu
Washington University School of Medicine
medinfo.wustl.edu