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NINDS to Support Eight New Parkinson's Disease Research Centers of Excellence

NINDS to Support Eight New Parkinson's Disease Research Centers of Excellence
NINDS to Support Eight New Parkinson's Disease Research Centers of Excellence


Duke Health News Duke Health News

As part of its efforts to defeat Parkinson's disease, the National Institute of Neurological Disorders and Stroke (NINDS) today announced plans to award new grants to eight top universities. The new awards will raise to eleven the number of Parkinson's Disease Research Centers of Excellence the Institute funds and represent a total commitment of $49 million to be spent over the next 5 years. Added to the $24 million committed to three such centers in September of 1998, this brings total Institute funding for the Parkinson's Disease Research Centers of Excellence program to $73 million.

"Opportunities for conquering Parkinson's disease have never been greater," says Gerald D. Fischbach, M.D., director of the NINDS. "We are confident that knowledge of the fundamental processes underlying this debilitating disease will, in turn, lead to improved diagnosis and treatment. The Centers' multidisciplinary framework provides the collaborative environment necessary to take full advantage of emerging discoveries in the basic and technological sciences that are the prelude to clinical advances. It is my hope that the scientists at the different Centers will work together whenever possible."

The Parkinson's Disease Research Centers of Excellence program was developed in response to Senate bill 535, also known as the Udall bill in honor of former Congressman Morris K. Udall, who died in December 1998 after a long battle with Parkinson's disease. In making today's announcement, Dr. Fischbach noted that the Centers will henceforth be called the Morris K. Udall Parkinson's Disease Research Centers of Excellence.

The eight new Udall Centers are located at Brigham and Women's Hospital Center for Neurologic Diseases in Boston, Massachusetts; the Neurological Institute at Columbia University in New York City; the University of Virginia Health System in Charlottesville; the Mayo Clinic in Jacksonville, Florida; the University of Kentucky in Lexington; Duke University in Durham, North Carolina; the University of California at Los Angeles (UCLA); and Harvard Medical School and McLean Hospital in Belmont, Massachusetts. They will join the NINDS Parkinson's Disease Research Center programs already under way at Emory University in Atlanta, Georgia; Massachusetts General Hospital in Boston; and The Johns Hopkins University School of Medicine in Baltimore, Maryland. Most of the Centers will also provide state-of-the-art, multidisciplinary training for young scientists preparing for research careers investigating Parkinson's disease and related neurodegenerative disorders.

Peter T. Lansbury, Jr., Ph.D., will lead the Parkinson's disease research team at the Brigham and Women's Hospital Center for Neurologic Diseases in Boston. The Massachusetts group seeks to elucidate the origins of Parkinson's disease by studying the structure and function of three proteins-alpha synuclein, ubiquitin C-hydrolase, and parkin-all of which are implicated in the development of two kinds of familial Parkinson's disease. Knowledge of how these proteins, which are the products of the mutant genes in these families, cause the clinical symptoms of Parkinson's disease should lead to the development of new drugs that target that process. The investigators also plan to develop new and better animal models to further study the pathogenesis of Parkinson's disease and screen potential therapeutic compounds.

Stanley Fahn, M.D., an international authority on Parkinson's disease, will oversee the Udall Center in New York City at the Neurological Institute at Columbia University. His group will use animal models and cell cultures to study various mechanisms of cell death, including the possible roles of hypochlorous acid, oxidative stress, and three proteins that may be involved in apoptosis, a kind of cellular suicide. Other members of the Columbia team hope to identify new genes that, when either expressed or suppressed, contribute to the degeneration of key nerve cells. In addition to conducting these basic studies, Center scientists will attempt to develop better methods for assessing the progression of Parkinson's disease using an imaging technique known as positron emission tomography, or PET. If they are successful, future clinical trials of therapeutic agents for Parkinson's disease could involve fewer patients and be completed more quickly than is currently the case. Finally, the New York group will investigate gender and ethnic differences in people with Parkinson's disease. Specifically, they will examine the role of risk factors in men versus women and blacks versus whites, studies which could lead to improved care for certain groups of patients.

In Charlottesville, scientists at the University of Virginia Health System will build upon their pioneering investigations of the role of mitochondrial mutations in Parkinson's disease. Mitochondria are microscopic, energy producers that function as "power plants" within cells. It has been suggested that specific mutations in mitochondrial DNA may be the cause of Parkinson's disease when it is not inherited. Under the direction of G. Frederick Wooten, M.D., the Charlottesville Center's research team will attempt to confirm this association, determine which mitochondrial defects are implicated, and define the mechanisms by which defective mitochondria may trigger cell death, oxidative stress, and other changes in Parkinson's disease.

John A. Hardy, Ph.D., is internationally known for his research on neurodegenerative disorders. His team at the Mayo Clinic's Jacksonville facility will attempt to clone two genes, one on chromosome 4 and one on chromosome 2, that are believed to be involved in familial forms of Parkinson's disease. Once the genes are cloned, their functions could be studied and the results evaluated for relevance to the more common, sporadic type of Parkinson's disease. The group will also endeavor to create a new and better mouse model that will clarify the role of alpha-synuclein and other proteins in cell death and degeneration. If successful, such a model could prove invaluable in studies of new treatments for Parkinson's disease.

It has been suggested that nerve growth factors, particularly GDNF, may be therapeutic in Parkinson's disease. Led by Greg A. Gerhardt, Ph.D., Udall Center scientists at the University of Kentucky will study the behavioral, functional, and anatomical effects of GDNF in a laboratory model of Parkinson's. Using an infusion pump, the investigators will deliver GDNF to two brain sites over a period of time to determine whether GDNF can protect or restore the function of damaged nerve cells without unwanted side effects. The group will also examine the effects of stopping and starting GDNF therapy. Such studies could lay the groundwork for human trials of GDNF and similar neuroprotective agents.

Jeffery M. Vance, M.D., will direct the Udall Center at Duke University. The Duke team will use several state-of-the-art methods to find genes that may contribute to the etiology of both the familial and sporadic types of Parkinson's disease. During autopsy of people with one of the two forms of the disease and of people without the disease, they will hunt for genes that are over-expressed or under-expressed in the substantia nigra, a part of the brain severely affected in Parkinson's disease. Such genes are likely to play a role in the cause of the disease. After the candidate genes are identified, the scientists will search for evidence of the genes in patients with either familial or sporadic Parkinson's disease and their siblings. Such research may allow investigators to distinguish the genes that contribute to familial Parkinson's from those involved in sporadic cases.

At UCLA, Marie-Francoise S. Chesselet, M.D., will lead studies designed to elucidate the role played by a part of the brain called the subthalamic nucleus in treated and untreated Parkinson's disease. It is believed that the loss of the brain chemical dopamine, a hallmark of Parkinson's disease, causes molecular and cellular changes in the subthalamic nucleus. Dr. Chesselet's group will compare the changes produced in the brains of rats with a Parkinson's-like disease when the animals are given one of three treatments: levodopa, the standard therapy for Parkinson's disease; deep brain stimulation; or implants of genetically engineered cells. They will then evaluate postmortem brain tissue from patients with Parkinson's to see whether the parkinsonian changes seen in the rat models also occurred in the patients. By clarifying the functional connections among the parts of the brain most affected in Parkinson's disease, such studies could pave the way for the development of new treatments for people with the disease.

Ole Isacson, M.D., will direct the Udall Center at Harvard University Medical School and McLean Hospital in Belmont, Massachusetts. His team will study several novel treatments for Parkinson's disease in animal models. One project will evaluate the ability of a new compound with neuroprotective properties to prevent and reverse parkinsonism in primates. Another project will expand on tissue implantation research. Previous implantation investigations have been limited to single transplants into the part of the brain called the striatum. Dr. Isacson's group will use a primate model to examine the effect of multiple fetal or stem cell implants into the striatum and the substantia nigra and subthalamic nucleus, other areas of the brain that are affected by the dopamine loss characteristic of Parkinson's disease. They will also transplant embryonic mouse tissue into rodent and primate Parkinson's models. Behavioral measurements, imaging studies using PET and magnetic resonance spectroscopy, and post-mortem tissue studies will be used to evaluate the efficacy of the therapies. Benefits seen in any of these animal studies could lead to clinical trials in humans with Parkinson's disease.

"The NINDS is dedicated to supporting a broad and varied program of Parkinson's disease research," says Dr. Fischbach. "Clinical breakthroughs are likely to come, not from one, but from a multitude of fields. It is our goal to provide the support necessary not only to conduct widely diversified Parkinson's disease research programs, but to foster collaboration and the open exchange of ideas among program investigators."

More than half a million Americans have Parkinson's disease, a neurological disorder of later life, that progressively impairs control of body movement, interferes with walking and talking, and often leads, over time, to rigid immobility. Symptoms of Parkinson's disease include tremor (particularly tremor of a body part at rest), stiff limbs, slow or absent movement, lack of facial expression, a shuffling gait, and a distinctive stoop. Other symptoms, such as depression and impaired ability to think, may also develop, especially during the later stages of the disease. These symptoms result from degeneration of nerve cells in the brain, particularly those involved in the production of the chemical dopamine. Although standard treatment with the drug combination levodopa/carbidopa can restore virtually normal movement to many people with Parkinson's early in the disease's course, the treatment loses effectiveness as the disease progresses.

The NINDS, part of the National Institutes of Health located in Bethesda, Maryland, is the nation's leading supporter of research on the brain and nervous system and a lead agency in the Congressionally designated Decade of the Brain. The NINDS celebrates its 50th anniversary in the year 2000.

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