E2F Family of Transcription Factors Involvement in Cell Death Following TBI

项目摘要/摘要 创伤性脑损伤(TBI)仍然是一个主要的公共卫生问题，影响到超过1.7 美国有一百万人。2010年，疾病控制中心估计 TBI的直接和间接成本为765亿美元。脑外伤患者的认知功能受损， 在脑外伤的动物模型中也观察到学习和记忆障碍。除了直接， 直接的原发损伤，延迟的分子和细胞变化导致细胞死亡和 颅脑损伤引起的神经功能障碍。一种得到很好支持的继发性损伤机制是细胞 循环激活(CCA)。脑损伤诱导的CCA导致有丝分裂后细胞凋亡，如 神经元和少突胶质细胞以及小胶质细胞的增殖，导致神经炎症 和继发性神经毒性。选择性细胞周期蛋白依赖性抑制CCA的药理作用 激酶抑制剂可阻止小胶质细胞和星形胶质细胞的激活，并改善认知功能。 已建立的受控皮质撞击的啮齿动物脑损伤模型将用于研究 抑制CCA背后的下游机制。拟议的研究将确定 选择性细胞周期抑制剂全身治疗对神经保护作用的潜力 CCA、小胶质细胞和星形胶质细胞激活，以及认知缺陷。了解 导致持续细胞死亡和认知缺陷的机制可能有助于 开发新的靶向治疗干预措施，潜在地提高生活质量 患有创伤性脑损伤的个体。

Project Summary/Abstract Traumatic brain injury (TBI) remains a major public health problem, effecting more than 1.7 million people in the United States. In 2010, the center for disease controlled estimated the direct and indirect costs of TBI were $76.5 billion. Patients with TBI have impaired cognition, learning and memory deficits are also observed in animal models of TBI. In addition to direct, immediate primary injury, delayed molecular and cellular changes contribute to cell death and neurological dysfunction caused by TBI. One well-supported secondary injury mechanism is cell cycle activation (CCA). TBI induced CCA results in apoptosis of post-mitotic cells such as neurons and oligodendroglial cells as well as microglia proliferation, causing neuroinflammation and secondary neurotoxicity. Pharmacological inhibition of CCA with selective cyclin-dependent kinase inhibitors prevents activation of microglia and astrocytes and improves cognitive function. The well-established rodent TBI model of controlled cortical impact will be used to investigate downstream mechanisms behind inhibiting CCA. The proposed research will determine the neuroprotective potential of systemic treatment with a selective cell cycle inhibitor to attenuate CCA, and microglial and astrocyte activation, and cognitive deficits. Understanding the mechanisms responsible for continued cell death and cognitive deficits may facilitate development of novel targeted therapeutic interventions potentially increasing the quality of life of individuals suffering from TBI.