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

• 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
• 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

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类型，每年在美国影响超过70，000例患者，但没有具体的治疗方法。出血部位先天免疫系统的刺激导致炎症和进行性脑损伤。在ICH的小鼠模型中，我们已经证明ICH导致血液来源的单核细胞和炎性单核细胞向血肿周围区域的募集以及小胶质细胞的活化和增殖。这些事件伴随进行性功能残疾。拟定的研究将利用转基因小鼠、骨髓嵌合体和体外试验来确定每个群体对ICH后免疫应答和功能结局的个体影响。具体目标1将确定CX3CR1+和CCR2+Gr1+单核细胞群体在ICH后损伤中的作用。在特定目标2中，将研究趋化因子受体CX3CR1和CCR2对小胶质细胞活化的作用。这些研究将共同确定靶向这些细胞反应在ICH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博士从指导到独立翻译研究员的培训。职业发展计划包括免疫学的正式课程，免疫学和神经科学的定期研讨会出席，以及会议的参与。这些教学内容将补充执行研究项目所涉及的培训，并为Sansing博士作为转化性卒中研究的独立研究者的职业生涯提供最佳定位。