Targeting Myeloid Populations to Reduce Injury after Intracerebral Hemorrhage

描述(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7万名患者，但目前还没有专门的治疗方法。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。在脑出血的小鼠模型中，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募集到血肿周围区域，并激活和增殖小胶质细胞。这些事件伴随着进行性功能残疾。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。具体目标1将确定CX3CR1+和CCR2+Gr1+单核细胞群在脑出血后损伤中的作用。在特定的目标2中，将研究趋化因子受体CX3CR1和CCR2在小胶质细胞激活中的作用。这些研究将共同确定Targein在治疗脑出血的这些细胞反应中的翻译潜力。这份提案概述了康涅狄格大学健康中心神经学助理教授Lauren Sansing医学博士从指导到独立翻译研究员的培训。职业发展计划包括正规的免疫学课程，定期参加免疫学和神经科学的研讨会，以及参加会议。这些教学部分将补充执行研究项目所涉及的培训，并为Sansing博士作为一名翻译中风研究的独立研究员的职业生涯提供最佳定位。

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.