Immune Mechanisms Regulating Cardiac Remodeling

摘要 心血管疾病是美国人的主要死因。大多数心血管疾病都是 与心肌质量增加或心肌肥厚相关。心脏对运动和 其他应激则通过增加心肌细胞的大小来产生更多的力量和应对 需求增加。除了在心肌细胞内激活的信号通路外，其他细胞 对心脏应激的反应会发生变化。其中一些变化是适应性的，但另一些是非适应性的。 尽管有许多治疗心力衰竭的方法可用，但我们仍然无法预防心脏功能不适应的改变。 对压力的反应。预防适应性不良的重塑可以最终避免心力衰竭。我们 使用创新技术获得了初步数据，显示巨噬细胞和B细胞 在心脏应激反应的早期适应阶段被激活。我们的假设是心脏住院医生 巨噬细胞在心脏应激过程中促进适应性、代偿性重塑 被B细胞感染。根据我们的初步发现，我们建议确定巨噬细胞在 病理和生理应激中心脏重构的早期适应阶段(目标1)，研究 肥大期间驻留巨噬细胞激活的来源和机制(目标2)，并确定 心脏应激期间B细胞影响巨噬细胞功能的机制(目标3)。在整个过程中 建议我们将使用创新技术，如单细胞RNA测序和先进成像 策略，探讨巨噬细胞和B细胞在心脏重构中的作用。当前的最终目标是 建议早期确定巨噬细胞在重塑过程中可能的适应性作用。使用这些 发现，未来的研究将集中在开发新的治疗方法，以增强适应性重塑和 抑制适应不良的重塑。考虑到心血管疾病对整体健康的影响，这项提案 为减轻心血管疾病对我们社会的负担带来了巨大的希望。

Summary Cardiovascular disease is the number cause of death in the United States. Most cardiovascular diseases are associated with an increase in myocardial mass or cardiac hypertrophy. The heart responds to exercise and other stress through an increase in cardiomyocyte in size in order to produce more force and cope with the increased demand. In addition to signaling pathways that are activated within cardiomyocytes, other cellular changes occur in response to cardiac stress. Some of these changes are adaptive but others are maladaptive. Although many therapies are available for heart failure, we are still not able to prevent maladaptive changes in response to stress. Prevention of maladaptive remodeling can lead to the ultimate avoidance of heart failure. We have acquired preliminary data using innovative technologies showing that macrophages and B cells are activated in the early adaptive phase in response to cardiac stress. Our hypothesis is that cardiac resident macrophages promote adaptive, compensatory remodeling during cardiac stress in a process that is regulated by B cells. Based on our preliminary findings, we are proposing to determine the role of macrophages in the early adaptive phase of cardiac remodeling during pathological and physiological stress (Aim 1), investigate the origins and mechanisms of resident macrophage activation during hypertrophy (Aim 2), and identify the mechanisms by which B cells influence macrophage function during cardiac stress (Aim 3). Throughout the proposal we will use innovative techniques, such as single-cell RNA sequencing and advanced imaging strategies, to probe the role of macrophages and B cells in cardiac remodeling. The ultimate goal of the current proposal is to identify a possible adaptive role of macrophage early during the remodeling process. Using these discoveries, future research will focus on developing novel therapeutics to enhance adaptive remodeling and inhibiting maladaptive remodeling. Given the impact of cardiovascular disease on overall health, this proposal holds great promise for reducing the burden of cardiovascular disease on our society.