Microglial Signal Transduction in Fever and Vasospasm after Subarachnoid Hemorrha

描述（由申请人提供）：Khalid Hanafy博士，医学博士，提出了一个5年的职业发展计划，研究小胶质细胞和炎症信号转导途径在蛛网膜下腔出血后发烧和血管痉挛产生中的作用。每年有3万美国人患有动脉瘤性蛛网膜下腔出血（aSAH）。目前对这些患者的治疗是有限的，因此aSAH的预后是令人沮丧的。在aSAH中，发热和血管痉挛（也称为延迟性脑缺血）值得进一步研究，因为在回顾性患者人群中，两者都是预后不良的预测因素。绝大多数aSAH患者有发热或血管痉挛，总体而言，每年有超过40%或12,000名aSAH患者死亡。由于发热和血管痉挛是预后不良的唯一可改变的危险因素，因此它们是未来治疗aSAH的重要目标。为此，阐明导致中枢性发热和血管痉挛的信号转导途径对于开发这种致命疾病的新疗法至关重要。在神经退行性疾病、脑出血和中枢性发热模型中；巨噬细胞或小胶质细胞是脑炎症的重要介质。本项目的具体目的是：(1)：检测小胶质细胞缺失小鼠的SAH是否比野生型小鼠的SAH有更少的中央性发热和血管痉挛。(2)：确定TLR4-MyD88通路是否为SAH患者发热和血管痉挛所必需。(3)：评估SAH后中枢性发热是否由神经元EP3受体介导。Hanafy博士是一名神经强化医生，凭借他在分子生物学和小动物模型方面的背景，他完全有资格研究这些问题。他对发烧与蛛网膜下腔出血的关系的研究是新颖的，并将得到发烧神经生物学基础专家Clifford Saper博士的大力支持。在这个项目中，他将接受额外的手术技术和数据解释方面的培训。此外，除了职业发展计划外，候选人还安排了与Saper博士的频繁会议，讨论项目进展情况。Hanafy博士的目标是通过更好地了解导致蛛网膜下腔出血后发烧和血管痉挛的分子机制，开发新的治疗蛛网膜下腔出血的方法。为了帮助他实现这一目标，哈纳菲博士召集了一个优秀的顾问小组，每年与他会面三次。他们包括神经内科主任Clifford Saper博士；Terry B. Strom博士，移植免疫学主任；以及血管生物学研究中心主任William C. Aird博士。Strom博士在移植介导现象中炎症转导通路的作用方面发表了大量文章，Aird博士正在研究不同形式的出血性中风及其对内皮细胞的影响。我们相信Hanafy博士有能力完成他的项目，并希望他能成为一名成功的NIH资助的研究者。

DESCRIPTION (provided by applicant): Dr. Khalid Hanafy, an MD, PhD, presents a 5 year career development plan to investigate the role of microglia and inflammatory signal transduction pathways in the production of fever and vasospasm after subarachnoid hemorrhage. Thirty thousand Americans have aneurysmal subarachnoid hemorrhage (aSAH) each year. Currently therapy for these patients is limited, and thus the prognosis for aSAH is dismal. In aSAH, fever and vasospasm, otherwise known as delayed cerebral ischemia, merit further study because both are predictors of poor outcome in retrospective patient populations. An overwhelming majority of aSAH patients have either fever or vasospasm, and, as a whole, more than 40% or 12,000 aSAH patients die each year. Because fever and vasospasm are the only modifiable risk factors for a poor outcome, they are an important target in the future treatment of aSAH. To this end, elucidation of the signal transduction pathways that lead to central fever and vasospasm are critical to the development of novel therapeutics for this deadly disease. In models of neurodegenerative disease, intracerebral hemorrhage, and central fever; an important mediator of cerebral inflammation is the resident macrophage or microglia. The Specific aims of this project are: (1): To examine whether SAH induced in microglia-depleted mice have less central fever and less vasospasm than SAH in wild type mice. (2): To determine if the TLR4-MyD88 pathway is required for fever and vasospasm in SAH. (3): To assess whether central fever after SAH is mediated by the neuronal EP3 receptor. Dr. Hanafy, a neurointensivist, is well-qualified to study these questions with his background in molecular biology and small animal models. His studies of fever as they relate to subarachnoid hemorrhage are novel and will be well-supported by Dr. Clifford Saper, an expert in the neurobiological basis of fever. He will be trained in additional surgical techniques and data interpretation during this project. Furthermore, the candidate has scheduled frequent meetings with Dr. Saper to discuss progress on the project, in addition to a plan for career development. Dr. Hanafy's goal is to develop novel therapeutic avenues for the treatment of subarachnoid hemorrhage through better understanding of the molecular mechanisms that lead to fever and vasospasm after subarachnoid hemorrhage. To help him accomplish this goal, Dr. Hanafy has assembled an excellent panel of advisors to meet with him three times a year. They include Dr. Clifford Saper, Chairman of the Department of Neurology; Dr. Terry B. Strom, Director of Transplant Immunology; and Dr. William C. Aird, Director of the Center for Vascular Biology Research. Dr. Strom has published extensively in the role of inflammatory transduction pathways in transplant mediated phenomenon and Dr. Aird is researching different forms of hemorrhagic stroke and their effects on the endothelial cell. We are confident that Dr. Hanafy has the tools to complete his project as outlined and hope he will become a successful NIH funded investigator.