Microglial Signal Transduction in Fever and Vasospasm after Subarachnoid Hemorrha

蛛网膜下腔出血后发热和血管痉挛中的小胶质细胞信号转导

• 批准号: 8868189
• 负责人: Khalid A. Hanafy
• 金额: $ 18.43万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8868189
• 关键词: Accounting; Agonist; American; Aneurysmal Subarachnoid Hemorrhages; Animal Model; Antibodies; Area Under Curve; Biology; Blood; Blood Vessels; Brain hemorrhage; Cerebral Ischemia; Cerebral hemisphere hemorrhage; Cerebrum; Chairperson; Clinical; Data; Development; Development Plans; Dinoprostone; Direct Costs; Disease; Doctor of Philosophy; Endothelial Cells; Erythrocytes; Evidence based treatment; Fever; Functional disorder; Funding; Future; Goals; Heme; Hypothalamic structure; Immunology; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Intraperitoneal Injections; Intraventricular; Lead; Ligands; Lipopolysaccharides; Location; Measures; Mediating; Mediator of activation protein; Microglia; Minority; Mitogen-Activated Protein Kinase Inhibitor; Mitogen-Activated Protein Kinases; Modeling; Molecular; Molecular Biology; Mus; Myelogenous; Neurobiology; Neurodegenerative Disorders; Neurology; Neurons; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Persons; Production; Prostaglandin Receptor; Prostaglandins; Proteins; Publishing; Qualifying; Reporting; Research; Research Personnel; Risk Factors; Role; Schedule; Signal Transduction; Signal Transduction Pathway; Stroke; Subarachnoid Hemorrhage; Subarachnoid Space; Targeted Research; Techniques; Therapeutic; Time; Training; Transplantation; United States National Institutes of Health; Vasospasm; Wild Type Mouse; base; career development; cyclooxygenase 2; improved; in vivo; irritation; macrophage; meetings; modifiable risk; mortality; novel; novel therapeutics; outcome forecast; patient population; preoptic nucleus; receptor; response; toll-like receptor 4; tool

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.

描述(申请人提供)：哈立德·哈纳菲博士，医学博士，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通路在蛛网膜下腔出血后发热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有限，因此ASAH的预后很差。在ASAH中，发热和血管痉挛，或称为延迟性脑缺血，值得进一步研究，因为在回顾患者群体中，两者都是不良预后的预测因素。绝大多数ASAH患者要么发烧，要么有血管痉挛，作为一个整体，每年有超过40%或12000名ASAH患者死亡。由于发热和血管痉挛是导致不良预后的唯一可改变的危险因素，因此它们是未来治疗ASAH的重要靶点。为此，阐明导致中枢性发热和血管痉挛的信号转导通路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的模型中，脑部炎症的一个重要媒介是常驻巨噬细胞或小胶质细胞。本项目的具体目的是：(1)检测小胶质细胞耗竭小鼠SAH是否比野生型SAH有更少的中枢性发热和血管痉挛。(2)：确定SAH发热和血管痉挛是否需要TLR4-MyD88通路。(3)探讨SAH后中枢发热是否由神经元EP3受体介导。哈纳菲博士是一名神经强化医生，他在分子生物学和小动物模型方面的背景，完全有资格研究这些问题。他对发烧与蛛网膜下腔出血有关的研究是新颖的，并将得到克利福德·萨珀博士的大力支持，萨珀博士是发烧的神经生物学基础专家。在这个项目中，他将接受其他外科技术和数据解释方面的培训。此外，这位候选人还安排了与萨珀博士的频繁会面，讨论该项目的进展情况，以及职业发展计划。Hanafy博士的目标是通过更好地了解蛛网膜下腔出血后导致发热和血管痉挛的分子机制，为蛛网膜下腔出血的治疗开发新的治疗途径。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。他们包括神经科主任克利福德·萨珀博士、移植免疫学主任特里·B·斯特罗姆博士和血管生物学研究中心主任威廉·C·艾尔德博士。斯特罗姆博士发表了大量关于炎症转导途径在移植介导的现象中的作用的文章，艾尔德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，哈纳菲博士拥有完成他概述的项目的工具，并希望他将成为一名成功的NIH资助的研究员。