Fas-Mediated Cell Death in TBI

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（受伤大脑的生理和神经化学反应）。我们的研究使我们更好地理解了可能导致TBI后早期和迟发性神经功能障碍的特定分子机制。在过去的五年里，该中心的研究人员已经发表了超过188篇同行评议的期刊文章和书籍章节。TBI启动病理生化级联反应，可以在生存后持续很长时间。增加对这些级联机制的理解以及通过可翻译疗法进行衰减是我们计划项目的主要科学目标。为该提案选择的具体项目代表了先前项目资助的主要研究者进行的研究的逻辑延伸，以及C博士引入的新探索领域。爱德华狄克逊。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在细胞死亡中与Ap的相互作用，（3）钙调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）iNOS内源性有益作用的机制。所有这些项目都包括临床相关的时间点，可翻译的治疗方法，以及至少一个测试基础科学假设与人类TBI相关性的特定目标。正因为如此，我们将能够将我们的初步调查结果与人类TBI相关联，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，我们的具体目标的完成可以预期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。

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.