Poly(ADP-Ribose) Polymerase and Brain Injury

描述(由申请人提供)： 匹兹堡大学脑创伤研究中心自1991年成立以来，一直在研究继发性脑损伤的分子和细胞机制(损伤脑的生理和神经化学反应)。我们的研究使人们对脑外伤后早期和迟发性神经功能障碍的具体分子机制有了更好的理解。该中心的调查人员在过去五年中撰写了188多篇同行评议的期刊文章和书籍章节。脑外伤会引发病理性的生化级联反应，在存活后很长一段时间内仍会持续。我们项目的主要科学目标是增加对这些级联反应机制的了解，并通过可翻译的疗法来减弱它们。为这项提案选择的具体项目代表了先前计划项目拨款的主要调查人员进行的研究的合乎逻辑的扩展，以及C.Edward Dixon博士引入的一个新的探索领域。这些研究包括(1)亚硝化应激和PARP激活，(2)他汀类药物治疗及其与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，以及(5)诱导型一氧化氮合酶内源性有益效应的机制(S)。所有的项目都包括临床上相关的时间点、可翻译的治疗方法，以及至少一个测试基本科学假设与人类脑损伤的相关性的具体目标。正因为如此，我们将能够将我们的初步研究结果与人类脑外伤联系起来，并确定它们在影响神经学结果方面的相对重要性。通过这种方式，我们的特定目标的完成可以预期确定继发性脑损伤的关键的急性和慢性分子机制，并确定最可能对脑外伤患者有益的治疗方法。

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.