E2F Family of Transcription Factors Involvement in Cell Death Following TBI

项目总结/摘要 创伤性脑损伤（TBI）仍然是一个主要的公共卫生问题， 在美国的百万人。2010年，疾病控制中心估计， TBI的直接和间接成本为765亿美元。创伤性脑损伤患者认知受损， 在TBI的动物模型中也观察到学习和记忆缺陷。除了直接， 直接的原发性损伤、延迟的分子和细胞变化导致细胞死亡， 脑外伤引起的神经功能障碍一个得到充分支持的继发性损伤机制是细胞 循环激活（CCA）。TBI诱导的CCA导致有丝分裂后细胞的凋亡， 神经元和少突胶质细胞以及小胶质细胞增殖，引起神经炎症 和继发性神经毒性。选择性细胞周期蛋白依赖性CCA的药理学抑制 激酶抑制剂防止小胶质细胞和星形胶质细胞的活化并改善认知功能。 将使用已建立的受控皮质撞击的啮齿动物TBI模型来研究 抑制CCA的下游机制。拟议的研究将确定 用选择性细胞周期抑制剂进行全身治疗以减弱 CCA、小胶质细胞和星形胶质细胞活化以及认知缺陷。了解 导致细胞持续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，可能提高生活质量 患有TBI的人。

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.