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: 8437024
• 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 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8437024
• 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; prostaglandin EP3 receptor; 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. PUBLIC HEALTH RELEVANCE: Even though a minority of the 795,000 strokes per year is due to aneurysmal subarachnoid hemorrhage (aSAH), it accounts for more than 50% of the annual direct cost of stroke per person and upwards of 68% mortality at one year. Vasospasm that leads to delayed cerebral ischemia requires further study because it occurs in 40% of aSAH patients. However, research targeting only vasospasm may not account for all clinical sequalae of aSAH that lead to poor outcome; such as fever, which also occurs in 40% of these patients. To develop novel Neuro-therapeutics for aSAH patients, the molecular mechanisms that lead to both fever and vasospasm need to be thoroughly understood to produce a complete picture of the pathophysiology of aSAH.

描述（由申请人提供）：医学博士、哲学博士 Khalid Hanafy 博士提出了一项为期 5 年的职业发展计划，旨在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热和血管痉挛产生中的作用。每年有三万名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（也称为迟发性脑缺血）值得进一步研究，因为两者都是回顾性患者群体预后不良的预测因素。绝大多数 aSAH 患者要么发烧，要么血管痉挛，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导致不良结果的唯一可改变的危险因素，因此它们是未来 aSAH 治疗的重要目标。为此，阐明导致中枢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；脑炎症的重要介质是常驻巨噬细胞或小胶质细胞。本项目的具体目的是： (1)：检查小胶质细胞缺失小鼠诱导的 SAH 是否比野生型小鼠的 SAH 具有更少的中枢发热和更少的血管痉挛。 (2): 确定SAH发热和血管痉挛是否需要TLR4-MyD88通路。 (3)：评估SAH后的中枢发热是否由神经元EP3受体介导。 Hanafy 博士是一名神经重症医师，凭借其分子生物学和小动物模型的背景，完全有资格研究这些问题。他对发烧与蛛网膜下腔出血相关的研究是新颖的，并将得到发烧神经生物学基础专家 Clifford Saper 博士的大力支持。在这个项目期间，他将接受额外的手术技术和数据解释的培训。此外，候选人还安排了与 Saper 博士的频繁会面，讨论项目进展以及职业发展计划。 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烧和血管痉挛的分子机制，开发治疗蛛网膜下腔出血的新治疗途径。为了帮助他实现这一目标，哈纳菲博士组建了一个优秀的顾问小组，每年与他会面 3 次。他们包括神经病学系主任 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，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 博士拥有完成其项目概述的工具，并希望他能成为一名成功的 NIH 资助的研究者。 公共健康相关性：尽管每年 795,000 例中风中的一小部分是由于动脉瘤性蛛网膜下腔出血 (aSAH)，但它占人均中风每年直接成本的 50% 以上，一年死亡率高达 68% 以上。导致迟发性脑缺血的血管痉挛需要进一步研究，因为它发生在 40% 的 aSAH 患者中。然而，仅针对血管痉挛的研究可能无法解释导致不良结果的 aSAH 的所有临床后遗症；例如发烧，其中 40% 的患者也会出现这种情况。为了开发针对 aSAH 患者的新型神经治疗药物，需要彻底了解导致发烧和血管痉挛的分子机制，以全面了解 aSAH 的病理生理学。