Calpain as a Therapeutic Target for TBI (P01)

本PPG的总体目标是评估这样一种假设，即Calain抑制代表着创伤性脑损伤(TBI)后干预的一个可行的治疗靶点。脑外伤是成人和儿童死亡和残疾的主要原因，迫切需要改进治疗方案。钙解痛症 在颅脑损伤后过度激活，与继发性神经元变性密切相关。 由此产生的假设是，抑制钙蛋白酶将保护脑损伤的病理和功能后果。尽管这一假设很简单，但事实证明，评估它出人意料地困难。在脑外伤动物模型中的一些研究表明，钙蛋白酶抑制剂治疗可以改善神经功能恢复和减轻轴突损伤。然而，有证据表明这些好处是 与钙蛋白酶抑制直接相关的问题一直难以捉摸。此外，关于钙调蛋白导致细胞死亡和功能障碍的机制，还有许多悬而未决的问题。这个PPG汇集了在钙蛋白酶生物化学和脑外伤动物模型方面具有丰富专业知识的研究人员，以评估 三种截然不同的机制抑制脑外伤后的钙蛋白。项目1探讨了内源性的、特异的和有效的钙蛋白酶抑制剂--钙蛋白酶抑制剂在调节钙蛋白酶功能和改善脑外伤后预后中的作用。项目2是翻译的，将研究新的小分子钙蛋白酶抑制剂的能力 减轻颅脑损伤的病理和功能后果。项目3将研究单个钙蛋白酶亚型在神经退行性变和脑外伤中的作用，重点是u-钙蛋白酶是一种病理亚型并定位于线粒体的假说。除了这三个项目外，还将有三个核心： A，行政和生物统计学核心；B，动物核心；和C，蛋白质组学和生物标记核心。总而言之，这些项目和核心将提供一个明确的迹象，表明抑制钙蛋白酶是否代表着一种可行的 脑外伤的治疗靶点，以及小分子钙蛋白酶抑制剂是否适合后续的临床前和临床研究。

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.