Arbor Vita proposes to determine the selectivity profiles of NMDA Receptors for PDZ domains and to identify selective inhibitors for use in reducing neuronal damage following a stroke. Stroke is a severe disorder that affects about 600,000 people a year in the United States and results in damage ranging from mild reduction in physical or cognitive function to death. Research has demonstrated that brain damage following stroke is the result of over-excitation of glutamate receptors, predominantly NMDA receptors. Independent labs have demonstrated that the functional association between neuronal nitric oxide synthase (nNOS) and NMDA Receptors occurs through the PDZ domain-containing protein PSD-95. Antagonists that block NMDA receptors show neuroprotection following damage; however, they have had severe side effects including coma and hallucinations. Peptides representing the C-terminus of NMDA Receptor 2B (Tat- NR2B9) demonstrated selective blocking of apoptosis without affecting calcium flux or electrical activity. This treatment resulted in neuroprotection without apparent cognitive compromise2. However, NMDA is known to bind to PDZs other than PSD95, suggesting that unappreciated side effects will probably be observed upon closer examination. AVC has a proprietary platform that contains all the PDZ domains present in the human genome that can be used to rapidly identify selective inhibitors. This proposal is directed at identifying specific lead compounds for neuroprotection following neurotrauma that target proteins downstream of NMDA Receptors and are selective and ready to enter cellular assays animal models and preclinical work. ? ?
