Myocardial-associated B lymphocytes and inflammatory injury

项目概要/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 在这种疾病的发展和进展中起着重要作用。但发展 迄今为止，基于免疫调节的心力衰竭治疗大多不成功。 PI最近描述了粘附于心肌内皮的循环B细胞群 发现缺乏B细胞的动物心脏结构和功能发生改变。此外，他发现 在啮齿类动物中，小分子介导的心肌B细胞调节可改善心脏移植后的心脏功能。 攻击这些发现，以及其他研究小组的新证据表明，B细胞可能 是开发免疫调节疗法以预防和治疗心脏病的有力靶点。 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。 心脏损伤引发局部和全身炎症反应，其特征在于招募 炎症细胞向受损的心脏和脾脏的快速变化。目前，还不清楚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， 心脏损伤引起的脾脏炎性变化已被证明在 虽然B细胞在心力衰竭的进展中起重要作用，但目前尚不清楚B细胞是否在脾免疫反应中起作用 心脏受损此外，B细胞介导的抗原呈递（即共同的抗原呈递） 抗体产生和细胞因子分泌是B细胞的3种典型功能之一）起任何作用 在心脏损伤引发的炎症反应中最后，在更基本的层面上， B细胞是如何粘附在未受损心脏的内皮上的。在这里，PI建议填补这些空白， 通过检验循环B细胞通过特异性结合心肌内皮细胞的假设， 粘附分子，并响应心肌损伤，通过CXCL 13-CCR 5进入心肌 依赖性过程，以抗原非依赖性方式被激活和增殖，并在 通过MHC-II介导的心脏和脾脏放大心脏损伤引起的炎症反应 抗原呈递PI的长期目标是利用获得的知识促进开发 B细胞靶向疗法治疗心力衰竭。 PI是研究B细胞与心脏相互作用的先驱。他是一个大三学生 虽然他是一名调查员，但他已经掌握了测试这一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，并在高度专业的环境中工作。 协作研究环境注重卓越和创新。因此，他完全有资格 有效地测试这一创新假设，并在本提案的时间轴内解决关键知识 描述的差距。

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.