Targeting Myeloid Populations to Reduce Injury after Intracerebral Hemorrhage

描述（由申请人提供）：脑出血（ICH）是一种破坏性的中风类型，每年在美国影响超过70,000名患者，但没有特定的治疗方法。刺激出血部位的先天免疫系统会导致炎症和进行性脑损伤。在小鼠脑出血模型中，我们已经证明脑出血导致血源性单核细胞和炎性单核细胞向血肿周围区域募集，以及小胶质细胞的激活和增殖。这些事件都伴随着进行性功能障碍。拟议的研究将利用转基因小鼠、骨髓嵌合体和体外试验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。特异性目的1将确定CX3CR1+和CCR2+Gr1+单核细胞群在脑出血后损伤中的作用。在Specific Aim 2中，将研究趋化因子受体CX3CR1和CCR2在小胶质细胞活化中的作用。这些研究将共同确定靶向这些细胞反应在脑出血治疗中的转化潜力。本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医学博士从导师到独立转化研究人员的培训。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的研讨会，以及参加会议。这些教学内容将补充参与执行研究项目的培训，并使Sansing博士成为转译性中风研究的独立研究者。

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.