Phenotype, dynamics and activation of myocardial B lymphocytes in response toischemia/reperfusion injury

项目摘要/摘要： 这项提议的目标是将首席调查员(PI)发展成为一名独立的医生 心血管研究领域的科学家。PI之前曾接受过发展方面的博士培训 他还获得了心血管基础研究和转化性研究方面的额外培训。在这一点上 时间，PI已经完成了内科、心脏病学、晚期心力衰竭和 他是道格拉斯博士的博士后研究员(由T32 HL007081支持) 曼恩实验室。以下五年职业发展计划将为PI提供免疫学方面的正式培训 以及正在进行的心脏损伤研究的实验室培训。在此授权期结束时，PI将 已经获得了成为一名独立和成功的内科科学家所需的技能。 华盛顿大学心脏科主任道格拉斯·曼博士将担任PI的主要导师。 曼恩博士是公认的心肌炎领域的领导者，在 心血管研究。他的专业知识横跨基础科学和临床科学，在临床科学中，他定义了 促炎症细胞因子在心力衰竭中的作用，并根据他的结果带头进行了临床试验。因此，他 是一个成功的内科科学家的完美范例，能够将基础科学研究 进入临床领域。国际和平研究所将利用这种指导以及巨大的基础科学 和华盛顿大学提供的临床资源(国际公认的顶级学者 机构)定义了一个与临床相关的基础科学研究的新领域。 心力衰竭是导致心血管疾病致残和死亡的主要原因之一。 单枪匹马地消耗了美国医疗保健总支出的近2%。最近的证据表明 心肌B淋巴细胞的调节可能提供一种创新的治疗方法，以减少 在经历过心脏损伤的患者中发生心力衰竭。不幸的是，我们目前 对心肌B淋巴细胞生物学的了解很少。我们最近发现，心肌B 淋巴细胞的异质性比以前认识到的要多得多。我们确定了几个 B细胞亚群，我们发现不同的B细胞亚群对 不同于急性心脏损伤。在这个方案中，我们将测试心肌中含有 具有不同个体发育的动态B淋巴细胞亚群，可产生对急性白血病的特异性反应 心脏损伤，B细胞在放大/分辨平衡中具有拮抗作用 心脏损伤的炎症反应。

Project Summary/Abstract: The goal of this proposal is to develop the Principal Investigator (PI) into an independent physician scientist in the field of cardiovascular research. The PI has previously obtained PhD training in developmental biology and has obtained additional training in basic and translational cardiovascular research. At this point in time, the PI has completed clinical training in Internal Medicine, Cardiology, Advanced Heart Failure and Cardiac Transplant and he is a post-doctoral research fellow (supported by T32 HL007081) in Dr. Douglas Mann’s Lab. The following 5-year career development plan will provide the PI formal training in immunology and ongoing laboratory training in the study of cardiac injury. At the conclusion of this award period, the PI will have acquired the skills necessary to become an independent and successful physician scientist. Dr. Douglas Mann, Chief of Cardiology at Washington University, will be the primary mentor of the PI. Dr. Mann is a recognized leader in myocardial inflammation and has a tremendous breadth of experience in cardiovascular research. His expertise spans from basic to clinical science where he has defined the role of pro-inflammatory cytokines in heart failure and spearheaded a clinical trial based on his results. As such, he serves as a perfect example of a successful physician scientist that is able to translate basic science research into the clinical arena. The PI will take advantage of this mentorship along with the enormous basic science and clinical resources available at Washington University (an internationally recognized premier academic institution) to define a new area of clinically relevant basic science research. Heart failure is one of the leading causes of disability and mortality related to cardiovascular disease and single handedly drains almost 2% of total US healthcare spending. Recent evidence suggests that modulation of myocardial B lymphocytes might provide an innovative therapeutic approach to reduce the development of heart failure in patients that experienced heart damage. Unfortunately, our current understanding of the biology of myocardial B lymphocytes is minimal. We recently found that myocardial B lymphocytes are much more heterogeneous than what was previously appreciated. We identified several subgroups of myocardial B cells and we showed that different sub-groups of myocardial B cells respond differently to acute heart damage. In this proposal, we will test the hypothesis that the myocardium harbors dynamic subpopulations of B lymphocytes with different ontogeny, that produce specific responses to acute cardiac injury, and that B cells have antagonistic roles within the amplification/resolution balance of the inflammatory response to cardiac damage.