Calpain as a Therapeutic Target for TBI (P01)

本PPG的总体目标是评价钙蛋白酶抑制代表一种可行的 创伤性脑损伤（TBI）后干预的治疗靶点。TBI是导致 成人和儿童的死亡和残疾，以及改进的治疗方案是迫切需要的。Calpains 在TBI后过度激活，并强烈参与继发性神经元变性。 由此产生的假设是，钙蛋白酶抑制剂将保护免受病理性和功能性损伤。 TBI的后果虽然简单明了，但这一假设已被证明是令人惊讶的困难， 评估。在TBI动物模型中的一些研究已经证明了神经恢复的改善 用钙蛋白酶抑制剂治疗减轻轴突损伤。然而，有证据表明，这些好处是 与钙蛋白酶抑制直接相关的研究一直是难以捉摸的。此外，还有许多未解之谜 关于钙蛋白酶导致细胞死亡和功能障碍的机制。PPG带来了 在钙蛋白酶生物化学和TBI动物模型方面具有丰富专业知识的研究人员一起评估 TBI后钙蛋白酶抑制的三种不同机制。项目1探讨了内源性、 钙蛋白酶抑制剂（calpastatin）在调节钙蛋白酶功能和改善预后中的作用 TBI之后。项目2是翻译，将研究新的小分子钙蛋白酶抑制剂的能力， 减轻TBI的病理和功能后果。项目3将审查以下方面的作用： 神经变性和TBI中的单个钙蛋白酶同种型，重点放在假设u-钙蛋白酶是一种 病理亚型，并定位于线粒体。除了这三个项目之外，还将有三个核心： A，管理和生物统计核心; B，动物核心;和C，蛋白质组学和生物标志物核心。在一起， 这些项目和核心将提供一个明确的指示，是否钙蛋白酶抑制剂代表一个可行的 TBI的治疗靶点，以及小分子钙蛋白酶抑制剂是否适用于随后的治疗。 临床前和临床研究。

The overall goal of this PPG is to evaluate the hypothesis that calpain inhibition represents a viable therapeutic target for intervention following traumatic brain injury (TBI). TBI represents a leading cause of death and disability in adults and children, and improved treatment options are urgently needed. Calpains are excessively activated following TBI and are strongly implicated in the secondary neuronal degeneration. The resultant hypothesis is that calpain inhibition will protect against the pathological and functional consequences of TBI. Although straightforward, this hypothesis has proven to be surprisingly difficult to evaluate. A handful of studies in animal models of TBI have demonstrated improved neurological recovery and attenuated axonal injury with calpain inhibitor treatment. However, evidence that these benefits are directly related to calpain inhibition has been elusive. Moreover, there are numerous unanswered questions regarding the mechanisms by which calpains contribute to cell death and dysfunction. This PPG brings together investigators with strong expertise in calpain biochemistry and in animal models of TBI to evaluate three distinct mechanisms of calpain inhibition following TBI. Project 1 explores the role of the endogenous, specific, and potent calpain inhibitor, calpastatin, in modulating calpain function and improving outcome following TBI. Project 2 is translational and will investigate the ability of new small molecule calpain inhibitors to attenuate the pathological and functional consequences of TBI. Project 3 will examine the roles of individual calpain isoforms in neurodegeneration and TBI, focusing on the hypothesis that u-calpain is a pathologic isoform and is localized to mitochondria. In addition to the three projects, there will be three cores: A, Administrative and Biostatistical Core; B, Animal Core; and C, Proteomics and Biomarker Core. Together, these projects and cores will provide a clear indication as to whether calpain inhibition represents a viable therapeutic target for TBI, and whether the small molecule calpain inhibitors are suitable for subsequent preclinical and clinical investigation.