Myocardial-associated B lymphocytes and inflammatory injury

心肌相关B淋巴细胞与炎症损伤

• 批准号: 10339541
• 负责人: Luigi Adamo
• 金额: $ 47.96万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10339541
• 关键词: Acute; Address; Adoptive Transfer; Affect; American; Animals; Anti-Inflammatory Agents; Antibodies; Antibody Formation; Antigen Presentation; Antigen Presentation Pathway; Antigens; B Cell Proliferation; B cell therapy; B-Cell Activation; B-Cell Antigen Receptor; B-Cell Development; B-Lymphocytes; Binding; Biology; CCR5 Signaling Pathway; CCR5 gene; CXCL13 gene; Cardiac; Cell Adhesion Molecules; Cells; Cellular biology; Chronic; Coculture Techniques; Data; Development; Disease; Disease Progression; Endothelial Cells; Endothelium; Environment; Goals; Heart; Heart Injuries; Heart failure; Histologic; Histology; Immune response; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injury; Innovative Therapy; Knowledge; Macaca; Mediating; Mus; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardial dysfunction; Myocardial tissue; Myocardium; P-selectin ligand protein; Pathway interactions; Patients; Pharmacology; Play; Population; Process; Proliferating; Reaction; Reperfusion Injury; Reporter; Reporting; Research; Research Personnel; Rodent; Role; Scientist; Seasons; Signal Transduction; Spleen; Splenectomy; Structure; System; Techniques; Testing; Therapeutic Intervention; TimeLine; Transgenic Mice; Transplantation; Vision; Work; base; cell motility; cytokine; experience; heart damage; heart function; human tissue; immunomodulatory therapies; immunoregulation; improved; in vivo; injured; innovation; intravital microscopy; myocardial injury; nonhuman primate; peripheral blood; prevent; rational design; recruit; response; single cell sequencing; small molecule; systemic inflammatory response; targeted treatment; therapeutic target

Project Summary/Abstract: Heart failure is a debilitating disease. A growing body of evidence indicates that inflammation plays an important role in the development and progression of this disease. However, the development of immunomodulatory based treatments for heart failure has, so far, been mostly unsuccessful. The PI recently described a population of circulating B cells that adheres to the myocardial endothelium and found that B cell deficient animals have alterations in cardiac structure and function. Moreover, he found that, in rodents, small molecule-mediated modulation of myocardial B cells improves cardiac function after heart attacks. These findings, together with emerging evidence from other research groups, suggest that B cells might be a powerful target for the development of immunomodulatory therapies to prevent and treat cardiac dysfunction. However, our current understanding of myocardial B cell biology is critically lacking. Heart damage triggers a local and systemic inflammatory response characterized by recruitment of inflammatory cells to the injured heart and rapid changes in the spleen. Currently, it is unclear if and how B cells are recruited into the injured myocardium. Moreover, even though B cells account for about half of all the cells in the spleen, and splenic inflammatory changes induced by heart damage have been shown to play a critical role in the progression of heart failure, it is unclear if B cells play a role in the splenic immune response triggered by heart damage. In addition, it remains unknown whether B cell mediated antigen presentation (that together with antibody production and cytokine secretion is one of the 3 prototypical functions of B cells) plays any role within the inflammatory response triggered by cardiac injury. Finally, at an even more basic level, it is unknown how B cells adhere to the endothelium of the uninjured heart. Here, the PI proposes to fill these gaps in knowledge by testing the hypothesis that circulating B cells bind to the myocardial endothelium through specific adhesion molecules and, in response to myocardial injury, enter the myocardium through a CXCL13-CCR5 dependent process, are activated and proliferate in an antigen independent manner, and recirculate between the heart and the spleen to amplify the inflammatory reaction elicited by cardiac damage via MHC-II mediated antigen presentation. The long-term goal of the PI is to use the knowledge gained to facilitate the development of B cell-targeted therapies for heart failure. The PI has been a pioneer in the study of the interaction between B cells and the heart. He is a junior investigator, but he has mastered all the techniques needed to test this hypothesis, he is supported by several seasoned scientists that are co-investigators or collaborators in this proposal, and works within a highly collaborative research environment focused on excellence and innovation. He, therefore, is aptly qualified to effectively test this innovative hypothesis and address, within the timeline of this proposal, the critical knowledge gaps described.

项目摘要/摘要： 心力衰竭是一种使人衰弱的疾病。越来越多的证据表明炎症在 在本病的发生和发展中发挥着重要作用。然而，发展 迄今为止，基于免疫调节的心力衰竭治疗大多不成功。 PI 最近描述了一群粘附在心肌内皮上的循环 B 细胞 并发现B细胞缺陷动物的心脏结构和功能发生改变。而且，他发现 在啮齿动物中，小分子介导的心肌 B 细胞调节可改善心脏功能 攻击。这些发现与其他研究小组的新证据一起表明 B 细胞可能 成为开发预防和治疗心脏病的免疫调节疗法的强大目标 功能障碍。然而，我们目前对心肌 B 细胞生物学的了解严重缺乏。 心脏损伤会引发局部和全身炎症反应，其特征是招募 炎症细胞到达受伤的心脏，脾脏迅速发生变化。目前，尚不清楚 B 细胞是否以及如何 被招募到受伤的心肌中。此外，尽管 B 细胞约占所有细胞的一半 在脾脏中，心脏损伤引起的脾脏炎症变化已被证明起着关键作用 B 细胞在心力衰竭进展中的作用，目前尚不清楚 B 细胞是否在触发的脾脏免疫反应中发挥作用 由心脏损伤。此外，B 细胞是否介导抗原呈递（一起 产生抗体和分泌细胞因子是 B 细胞的 3 个典型功能之一）发挥任何作用 心脏损伤引发的炎症反应。最后，在更基本的层面上，这是未知的 B 细胞如何粘附到未受伤心脏的内皮上。在此，PI 建议填补这些空白 通过测试循环 B 细胞通过特定的方式与心肌内皮结合的假设来获得知识 粘附分子，响应心肌损伤，通过 CXCL13-CCR5 进入心肌 依赖性过程，以不依赖于抗原的方式激活和增殖，并在 心脏和脾脏通过 MHC-II 介导放大心脏损伤引起的炎症反应 抗原呈递。 PI 的长期目标是利用所获得的知识来促进开发 B细胞靶向治疗心力衰竭的研究进展。 PI 一直是 B 细胞与心脏相互作用研究的先驱。他是一名小三 调查员，但他已经掌握了检验这个假设所需的所有技术，他得到了几个人的支持 经验丰富的科学家是本提案的共同研究者或合作者，并且在高度合作的范围内工作 注重卓越和创新的协作研究环境。因此，他完全有资格 有效地测试这一创新假设，并在该提案的时间表内解决关键知识 所描述的差距。