Poly(ADP-Ribose) Polymerase and Brain Injury

聚（ADP-核糖）聚合酶与脑损伤

• 批准号: 7131002
• 负责人: Robert S B Clark
• 金额: $ 15.72万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-15 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7131002
• 关键词: ADP ribosylation; DNA damage; apoptosis; brain; brain injury; cell death; death; human; lead; memory; proteins; role; success

DESCRIPTION (provided by applicant): The University of Pittsburgh Brain Trauma Research Center has been investigating the molecular and cellular mechanisms of secondary brain injury (physiologic and neurochemical responses of the injured brain) since its inception in 1991. Our studies have lead to an improved understanding of specific molecular mechanisms likely to be responsible for early and delayed neurologic dysfunction following TBI. The investigators of the Center have resulted in more than 188 peer-reviewed journal articles and book chapters during the last five years. TBI initiates pathological biochemical cascades that can persist long after survival. An increased understanding of the mechanisms of these cascades and their attenuation by translatable therapies are the primary scientific goals of our program project. The specific projects selected for this proposal represent a logical extension of the research conducted by primary investigators of the previous program project grant, as well as a new area of exploration introduced by Dr. C. Edward Dixon. These include the study of (1) nitrosative stress and PARP activation, (2) statins therapies and their interaction with Ap in cell death, (3) effects of calcineurin inhibition on neuronal death and plasticity, (4) Fas-mediated cell death, and (5) mechanism(s) underlying the endogenous beneficial effects of iNOS. All of the projects include clinically relevant time points, translatable treatments, and at least one specific aim that test the relevance of the basic science hypotheses to TBI in humans. Because of this we will be able to correlate the findings of our primary investigations with human TBI and determine their relative importance in effecting neurologic outcome. In this way, the completion of our specific aims can be expected to define critical acute and chronic molecular mechanisms of secondary brain injury and identify treatments most likely to be beneficial to TBI patients.

描述（由申请人提供）： 自1991年成立以来，匹兹堡大学脑创伤研究中心一直在研究脑损伤（生理学和神经化学反应的生理和神经化学反应）的分子和细胞机制。我们的研究已导致对特定的分子机制的不断了解，可能会导致对特定的分子机制的早期和延迟的神经系统作用。该中心的调查人员在过去五年中收到了188多个同行评审的期刊文章和书籍章节。 TBI启动了可能在生存后很长时间持续存在的病理生化级联。对这些级联反应的机制及其通过可翻译疗法的衰减的越来越多的理解是我们计划项目的主要科学目标。为该提案选择的特定项目代表了先前计划项目赠款的主要研究人员进行的研究的逻辑扩展，以及C. Edward Dixon博士引入的新探索领域。其中包括（1）硝化应激和PARP激活的研究，（2）他汀类药物疗法及其与AP在细胞死亡中的相互作用，（3）钙调蛋白抑制对神经元死亡和可塑性的影响，（4）FAS介导的细胞死亡，以及（5）INOS内源性有益作用的机制。所有项目都包括临床相关时间点，可翻译的治疗方法以及至少一个特定的目标，这些目标测试了基础科学假设与人类中TBI的相关性。因此，我们将能够将我们的主要研究结果与人类TBI相关联，并确定它们在影响神经系统结果中的相对重要性。通过这种方式，可以预期我们的特定目标的完成将定义继发性脑损伤的关键急性和慢性分子机制，并确定最有可能对TBI患者有益的治疗方法。