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

心肌 B 淋巴细胞响应缺血/再灌注损伤的表型、动力学和激活

• 批准号: 10261534
• 负责人: Luigi Adamo
• 金额: $ 15.06万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10261534
• 关键词: Acute; Adult; Area; Award; B-Lymphocytes; Basic Science; Biology; Bone Marrow; Cardiac; Cardiology; Cardiovascular Diseases; Cardiovascular system; Cellular biology; Clinical; Clinical Sciences; Clinical Trials; Dendritic Cells; Development; Development Plans; Developmental Biology; Disease; Doctor of Philosophy; Embryo; Embryonic Development; Equilibrium; Goals; Growth; Handedness; Health; Healthcare; Heart; Heart Injuries; Heart Transplantation; Heart failure; Heterogeneity; Immunology; Immunomodulators; Inflammation; Inflammatory; Inflammatory Response; Injury; Innate Immune Response; Innate Immune System; Institution; Internal Medicine; International; Knowledge; Lead; Lymphocyte Function; Mediating; Mentors; Mentorship; Monoclonal Antibodies; Myocardial; Myocardial dysfunction; Myocardial tissue; Myocardium; Patients; Phenotype; Physicians; Play; Population; Postdoctoral Fellow; Principal Investigator; Reperfusion Injury; Research; Resolution; Resources; Role; Scientist; Subgroup; T-Lymphocyte; Testing; Therapeutic; Time; Training; Translating; Universities; Washington; Work; base; cardiac repair; cardiogenesis; cardiovascular effects; career development; clinically relevant; cytokine; disability; experience; healthy aging; heart damage; immunomodulatory strategy; immunoregulation; innovation; laboratory experience; macrophage; monocyte; mortality; myocardial injury; prevent; response; side effect; skills; small molecule; stem; therapeutic target; tissue injury; tissue repair; trafficking; translational study

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.

项目摘要/摘要： 该提案的目标是将首席研究员（PI）培养成为一名独立的医生 心血管研究领域的科学家，曾获得发育学博士学位。 生物学，并已获得基础和转化心血管研究的额外培训。 此时，PI 已完成内科、心脏病学、晚期心力衰竭和 心脏移植，他是道格拉斯博士的博士后研究员（由T32 HL007081支持） 曼恩实验室接下来的 5 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实验室培训。在本奖励期结束时，PI 将 已获得成为独立且成功的医师科学家所需的技能。 华盛顿大学心脏病学主任 Douglas Mann 博士将担任 PI 的主要导师。 Mann 博士是心肌炎症领域公认的领导者，在以下领域拥有丰富的经验： 他的专业知识涵盖基础科学和临床科学，并定义了心血管研究的作用。 他研究了心力衰竭中的促炎细胞因子，并根据他的结果领导了一项临床试验。 是一位成功的医学科学家能够转化基础科学研究的完美典范 PI 将利用这种指导以及大量的基础科学。 华盛顿大学（国际公认的一流学术机构）提供的临床资源 机构）来定义临床相关基础科学研究的新领域。 心力衰竭是与心血管疾病相关的残疾和死亡的主要原因之一 最近的证据表明，这一支出占美国医疗保健支出总额的近 2%。 心肌 B 淋巴细胞的调节可能提供一种创新的治疗方法来减少 不幸的是，我们目前经历过心脏损伤的患者会出现心力衰竭。 我们对心肌 B 淋巴细胞的生物学了解甚少。 淋巴细胞的异质性比我们之前认识到的要高得多。 心肌 B 细胞亚群，我们发现心肌 B 细胞的不同亚群有反应 与急性心脏损伤不同，在本提案中，我们将检验心肌存在的假设。 具有不同个体发育的 B 淋巴细胞动态亚群，对急性应激反应产生特异性反应 心脏损伤，并且 B 细胞在放大/分辨率平衡中具有拮抗作用 对心脏损伤的炎症反应。