A Novel Drug To Reduce Neronal Damage Following Stroke

描述（由申请人提供）：Arbor Vita提议确定NMDA受体对PDZ结构域的选择性概况，并确定用于减少中风后神经元损伤的选择性抑制剂。中风是一种严重的疾病，在美国每年约有60万人受到影响，其后果从轻微的身体或认知功能下降到死亡不等。研究表明，脑卒中后的脑损伤是谷氨酸受体过度兴奋的结果，主要是NMDA受体。独立实验室已经证明神经元一氧化氮合酶（nNOS）和NMDA受体之间的功能关联是通过含有PDZ结构域的蛋白PSD-95发生的。阻断NMDA受体的拮抗剂在损伤后显示神经保护作用；然而，它们有严重的副作用，包括昏迷和幻觉。代表NMDA受体2B c端（Tat- NR2B9）的多肽在不影响钙通量或电活性的情况下选择性阻断细胞凋亡。这种治疗产生了神经保护，但没有明显的认知损害2。然而，已知NMDA与PSD95以外的pdz结合，这表明在仔细检查后可能会观察到未被注意到的副作用。AVC拥有一个专有平台，包含人类基因组中存在的所有PDZ结构域，可用于快速识别选择性抑制剂。该建议旨在识别神经损伤后神经保护的特定先导化合物，这些化合物针对NMDA受体下游的蛋白质，具有选择性，可用于细胞分析、动物模型和临床前工作。

DESCRIPTION (PROVIDED BY APPLICANT): 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.