Immune Mechanisms Regulating Cardiac Remodeling

总结 心血管疾病是美国死亡的主要原因。大多数心血管疾病是 与心肌质量增加或心脏肥大相关。心脏对运动有反应， 其他压力通过增加心肌细胞的大小，以产生更多的力量和科普 需求增加。除了在心肌细胞内激活的信号传导途径外，其他细胞信号传导途径也被激活。 变化是对心脏应激的反应。其中一些变化是适应性的，但另一些是适应不良的。 虽然有许多治疗心力衰竭的方法，但我们仍然无法防止适应不良的变化， 对压力的反应。预防适应不良的重塑可以最终避免心力衰竭。我们 已经使用创新技术获得了初步数据，表明巨噬细胞和B细胞是 在早期适应阶段对心脏应激的反应中被激活。我们的假设是心脏科住院医师 巨噬细胞在心脏应激过程中促进适应性、代偿性重塑， 由B细胞产生。基于我们的初步发现，我们建议确定巨噬细胞在 在病理和生理应激过程中心脏重构的早期适应阶段（目的1）， 肥大期间常驻巨噬细胞活化的起源和机制（目的2），并确定 心脏应激过程中B细胞影响巨噬细胞功能的机制（目的3）。在整个 我们将使用创新技术，如单细胞RNA测序和先进的成像技术， 策略，以探测巨噬细胞和B细胞在心脏重塑中的作用。当前的最终目标 建议是在重塑过程的早期确定巨噬细胞可能的适应性作用。使用这些 发现，未来的研究将集中在开发新的疗法，以加强适应性重塑， 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， 为减轻心血管疾病给我们社会带来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.