nNOS-PSD95 inhibitors as novel treatments for TBI

 描述（由申请人提供）：本申请“nNOS-PSD 95抑制剂作为TBI的新型治疗”解决了对创伤性脑损伤（TBI）有效治疗的迫切需求。TBI是美国最活跃人群（<45岁）死亡和残疾的主要原因。不幸的是，还没有开发出有效的药物干预措施。因此，迫切需要了解TBI后功能缺陷的分子机制，并将这些知识转化为新的TBI治疗方法的开发。在TBI中，NMDA谷氨酸受体（NMDAR）的激活刺激神经元型一氧化氮合酶（nNOS），并最终增加信号分子一氧化氮（NO）。突触后密度蛋白（PSD 95）是将nNOS定位在NMDAR附近所必需的，因此是nNOS的NMDAR激活所必需的。这种NMDAR-PSD 95-nNOS级联与TBI后的功能缺陷有关。Anagin是一家位于印第安纳州的小企业，其在印第安纳州大学医学院的研究合作伙伴的初步结果表明，nNOS和PSD 95之间相互作用的小分子抑制剂在TBI的临床前模型中具有神经保护作用。该I期SBIR计划的具体目的是通过充分表征治疗的剂量反应和治疗窗口来测试在TBI的临床前模型中抑制nNOS-PSD 95相互作用的功能益处。如果成功，该项目将验证TBI干预的新目标和机制。未来的II期SBIR研究将确定Anagin目前正在开发的新nNOS-PSD 95抑制剂是否是治疗TBI的潜在药物开发候选药物。

 DESCRIPTION (provided by applicant): This application "nNOS-PSD95 inhibitors as novel treatments for TBI" addresses the critical need for an efficacious treatment for traumatic brain injury (TBI). TBI is the leading cause of death and disability in the most active population (<45 years of age) in the United States. Unfortunately, no effective pharmaceutical interventions have been developed. Thus, there is a critical need to understand the molecular mechanisms underlying functional deficits after TBI as well as to translate this knowledge into the development of new TBI treatments. In TBI, activation of the NMDA glutamate receptor (NMDAR) stimulates the enzyme neuronal nitric oxide synthase (nNOS) and, ultimately, increases the signaling molecule nitric oxide (NO). Postsynaptic density protein (PSD95) is necessary to position nNOS close to the NMDAR and is therefore required for NMDAR activation of nNOS. This NMDAR-PSD95-nNOS cascade is implicated in the functional deficits following TBI. Anagin, an Indiana-based small business, and its research partners at Indiana University School of Medicine have preliminary results suggesting that a small molecule inhibitor of the interaction between nNOS and PSD95 is neuroprotective in a preclinical model of TBI. The specific aim for this Phase I SBIR program is to test the functional benefits of inhibiting nNOS-PSD95 interaction in a preclinical model of TBI by fully characterizing the dose response and therapeutic window of treatment. If successful, this project will validate a new target and mechanism for intervention for TBI. Future Phase II SBIR studies will determine if the new nNOS-PSD95 inhibitors currently being developed by Anagin are potential drug development candidates for the treatment of TBI.