nNOS-PSD95 inhibitors as novel treatments for TBI

 描述(由申请人提供)：这项名为“nNOS-PSD95抑制剂作为治疗脑创伤的新疗法”的申请满足了对创伤性脑损伤(TBI)有效治疗的迫切需要。在美国最活跃的人群(45岁)中，脑外伤是导致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，迫切需要了解脑外伤后潜在的功能障碍的分子机制，并将这一知识转化为新的脑损伤治疗方法的开发。在脑损伤中，NMDAR的激活刺激了神经元型一氧化氮合酶(NNOS)，最终增加了信号分子一氧化氮(NO)。突触后密度蛋白(PSD95)是将nNOS定位在NMDAR附近所必需的，因此也是NMDAR激活nNOS所必需的。这种NMDAR-PSD95-nNOS级联反应与脑损伤后的功能缺陷有关。总部位于印第安纳州的小企业Anagin及其在印第安纳大学医学院的研究伙伴的初步结果表明，nNOS和PSD95之间相互作用的小分子抑制剂在临床前脑损伤模型中具有神经保护作用。这一第一阶段SBIR计划的具体目的是通过充分描述剂量反应和治疗窗口，在临床前脑损伤模型中测试抑制nNOS-PSD95相互作用的功能益处。如果成功，该项目将验证一个新的脑损伤干预目标和机制。未来的第二阶段SBIR研究将确定Anagin目前正在开发的新的nNOS-PSD95抑制剂是否为治疗脑损伤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.