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）： 匹兹堡大学脑外伤研究中心自 1991 年成立以来一直在研究继发性脑损伤（受伤大脑的生理和神经化学反应）的分子和细胞机制。我们的研究使人们更好地了解了可能导致继发性脑损伤的特定分子机制。导致 TBI 后早期和迟发性神经功能障碍。该中心的研究人员在过去五年中发表了超过 188 篇经过同行评审的期刊文章和书籍章节。 TBI 引发病理生化级联反应，这种级联反应在存活后仍能持续很长时间。加深对这些级联机制的了解以及通过可转化疗法减弱它们的作用是我们项目的主要科学目标。本提案选择的具体项目代表了先前项目项目资助的主要研究人员进行的研究的逻辑延伸，以及 C. Edward Dixon 博士引入的新探索领域。这些包括 (1) 亚硝化应激和 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) 钙调神经磷酸酶抑制对神经元死亡和可塑性的影响，(4) Fas 介导的细胞死亡， (5) iNOS 内源性有益作用的机制。所有项目都包括临床相关的时间点、可转化的治疗方法以及至少一个测试基础科学假设与人类 TBI 相关性的具体目标。因此，我们将能够将我们的初步研究结果与人类 TBI 相关联，并确定它们在影响神经系统结果方面的相对重要性。通过这种方式，我们的具体目标的完成有望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。