Barry W. Festoff, M.D. Director

NBRL 151
VA Medical Center
4801 Linwood Blvd.
Kansas City, MO 64128-2295

serpin@eagle.cc.ukans.edu

816-861-4700 x7079
816-922-3375 Fax

Barry W. Festoff, M.D., is Staff Neurologist and Director of the Neurobiology Research Laboratory (NBRL) at the Veterans Heartland Heath Service Network Medical Center in Kansas City, MO and Professor, Departments of Neurology and Pharmacology, Toxicology and Therapeutics, at the University of Kansas School of Medicine. Dr. Festoff has been in Federal service for 32 years, and with the VA for 23 years, having established a major research unit at the Medical Center conducting basic and applied research in the pathobiology of neurologic illnesses. The NBRL has been continuously funded by VA Merit Review for over 20 years, and over the years by NIH, NSF, DoD as well as Alzheimer's, ALS, Muscular Dystrophy and Parkinson's disease agencies. Dr. Festoff currently supervises two Research Assistant Professors, three Postdoctoral Fellows, and six other master's and bachelor's degree research employees.

The NBRL is currently working on four main projects: a Merit Review entitled, "Strategies to reverse neuronal death in aging, disease and trauma" that continues until 2002; a Merit Review entitled "Inclusion body formation in Parkinson's and related diseases" that continues until 2003; a contract with the Uniformed Services University of the Health Sciences, Bethesda, MD to determine the role of proteases and their inhibitors in head injury; a grant from the Christopher Reeves Paralysis Foundation entitled "Innovative approaches to cell loss in injured spinal cord" that continues until 2001 and a partnership with Cephalon, Inc., West Chester, PA to investigate the role of insulin-like growth factors in Amyotrophic Lateral Sclerosis.

Dr. Festoff has recently returned to the United States having spent a Visiting Professor ship in the Laboratoire de Plasticité Cérébrale ERS 5644 du CNRS at the Université Montpellier II with Professor Max Recasens there investigating thrombin's effects on neurons and astrocytes of embryonic rat hippocampi. He also had a sabbatical year in France (September 1994-August 1995) and was Professeur et Chaire (Elf Aquitaine) de l'Academie des Sciences Francaise at INSERM Unité 153, Paris, Hôpital Salpètrière. While in Paris during that time he developed a model for the expression and measurement of molecules associated with Alzheimer's disease on the surface of blood platelets. A previous sabbatical with the same group in 1984-85 resulted in a number of collaborative papers on the role of serine proteases and their inhibitors (serpins) in neuromuscular junction formation and pathology.

Dr. Festoff has made major contributions to our understanding of the role of proteases, such as thrombin, in degeneration of the neuromuscular synapse. An early model he proposed hypothesized a protective role of protease inhibitors in synapse loss due to proteases. An animal model used by Dr. Festoff has also yielded similar results. Mice are used to study the natural programmed elimination of polyneuronal synapses. Shortly after birth, all vertebrates which possess muscle fibers innervated by multiple nerve axons undergo a process of programmed elimination so that unnecessary synapses are "pruned" resulting in a muscle fiber that is innervated by one neuron alone. The NBRL had found that elimination of the polyneuronal innervation state can be prevented with thrombin inhibitors, such as protease nexin I and hirudin, a specific thrombin inhibitor from the leech, thus implicating this enzyme in elimination of polyneuronal innervation. It is likely that the molecular processes that underlies polyneuronal elimination may also be implicated in synapse loss in neurodegenerative diseases. An understanding of the molecular bases of polyneuronal elimination may lead to an understanding of how to prevent or treat such conditions as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and Parkinson's (PD) diseases.

As an approach to the latter, Dr. Festoff and colleagues at the NBRL, particularly Dr. Bruce Citron, have found that the bi-functional enzyme tissue transglutaminase (tTG) may be implicated in inclusion body formation (Lewy bodies) that are hallmarks of PD victim's brains. In addition to Lewy body formation, tTG may also be involved in the aggregates known as neurofibrillary tangles (NFTs) in hippocampal neurons in AD and in the spheroids or conglomerates found in motor neurons in ALS. Elevated tTG activity may cross-link essential neuronal proteins in these diseases such as the neurofilament (NF), amyloid precursor (APP) and alpha synuclein proteins. Similar aggregation is known to occur in Huntington's disease and in similar genetic disorders of the nervous system known as CAG triplet or polyglutamine repeat diseases.

Finally, these studies are all designed to develop new paradigms for preserving neuronal life and function, known generally as neuroprotection and neurorepair are significant therapeutic goals that the NBRL concentrates on and utilizes these novel molecular approaches.