Targeting Myeloid Populations to Reduce Injury after Intracerebral Hemorrhage

靶向骨髓细胞以减少脑出血后的损伤

基本信息

批准号：
8901319
负责人：
LAUREN H SANSING
金额：
$ 18.74万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-03 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8901319
关键词：
Affect Agonist Anti-Inflammatory Agents Anti-inflammatory Blood Bone Marrow Brain Brain Injuries CCL2 gene CX3CL1 gene Cells Central Nervous System Diseases Cerebral hemisphere hemorrhage Chemotaxis Chimera organism Complement Connecticut Cytokine Activation Development Plans Disabled Persons Disease model Event Fibrinogen Flow Cytometry Gelatinase B Goals Health Hematopoietic Hemorrhage Hour Immune Immune response Immune system Immunohistochemistry Immunology Individual Infiltration Inflammation Inflammation Mediators Inflammatory Inflammatory Infiltrate Inflammatory Response Injury Investigation Iron Ischemic Stroke Knockout Mice Lead Left Leukocytes Long-Term Effects Measures Mediating Mentors Microglia Modeling Mus Myelogenous Myeloid Cells Neurology Neurosciences Neutrophil Activation Outcome Pathway interactions Patients Phagocytosis Population Positioning Attribute Production Receptor Activation Recombinants Recovery Research Research Personnel Research Project Grants Risk Role Signal Transduction Site Staining method Stains Stimulus Stroke Testing Therapeutic Intervention Thrombin Time Training Transgenic Mice Universities Western Blotting Work career career development cell type chemokine chemokine receptor cytokine disability functional disability functional outcomes gait examination improved in vitro Assay in vivo monocyte neurobehavioral neuron loss neuroprotection professor progenitor receptor response symposium therapeutic target toll-like receptor 4 trafficking

项目摘要

DESCRIPTION (provided by applicant): Intracerebral hemorrhage (ICH) is a devastating type of stroke affecting more than 70,000 patients in the U.S. each year, yet there is no specific treatment available. Stimulation of the innate immune system at the site of hemorrhage leads to inflammation and progressive brain injury. In a murine model of ICH, we have demonstrated that ICH leads to the recruitment of blood-derived monocytes and inflammatory monocytes to the perihematomal region and the activation and proliferation of microglia. These events are concomitant with progressive functional disability. The proposed studies will utilize transgenic mice, bone marrow chimeras, and in vitro assays to determine the individual effects of each population on the immune response and functional outcomes after ICH. Specific Aim 1 will determine the roles of the CX3CR1+ and CCR2+Gr1+ monocyte populations in injury after ICH. In Specific Aim 2, the role of chemokine receptors CX3CR1 and CCR2 on microglial activation will be investigated. Together these studies will determine the translational potential of targetin these cellular responses in the treatment of ICH. This proposal outlines the training of Lauren Sansing, MD, an Assistant Professor in Neurology at the University of Connecticut Health Center, from mentored to independent translational researcher. Career development plans include formal coursework in immunology, regular seminar attendance in both immunology and neuroscience, and conference participation. These didactic components will complement the training involved in executing the research project and optimally position Dr. Sansing for a career as an independent investigator in translational stroke research.

描述（由申请人提供）：脑出血 (ICH) 是一种毁灭性的中风，每年影响美国超过 70,000 名患者，但目前尚无特效治疗方法。出血部位先天免疫系统的刺激会导致炎症和进行性脑损伤。在脑出血的小鼠模型中，我们证明脑出血会导致血源性单核细胞和炎性单核细胞募集到血肿周围区域，并导致小胶质细胞的激活和增殖。这些事件伴随着进行性功能障碍。拟议的研究将利用转基因小鼠、骨髓嵌合体和体外测定来确定每个群体对脑出血后免疫反应和功能结果的个体影响。具体目标 1 将确定 CX3CR1+ 和 CCR2+Gr1+ 单核细胞群在 ICH 后损伤中的作用。在具体目标 2 中，将研究趋化因子受体 CX3CR1 和 CCR2 对小胶质细胞激活的作用。这些研究将共同确定这些细胞反应中的靶点在脑出血治疗中的转化潜力。该提案概述了康涅狄格大学健康中心神经病学助理教授 Lauren Sansing 医学博士从受指导到独立转化研究员的培训。职业发展计划包括免疫学的正式课程、定期参加免疫学和神经科学研讨会以及参加会议。这些教学内容将补充执行研究项目所涉及的培训，并为 Sansing 博士作为转化性中风研究的独立研究者提供最佳的职业定位。