Scarring and Arrhythmia in Infarcted Aged Hearts: Role of Senescent Fibroblasts

衰老与心源性猝死（SCD）发生率增加10倍以上相关。蜂窝 衰老是以增殖能力的不可逆丧失为特征的应激反应， 伴随着复杂的衰老相关分泌表型（SASP）， 对组织中邻近细胞的影响。我们的研究计划基于以下主要前提。第一个 纤维化是心脏损伤（心肌梗塞）的结果 瘢痕中的炎症过程可能使心脏易患心律失常。二是 心脏成纤维细胞（CF）的细胞衰老在MI后伤口愈合中起重要作用。的 我们提出的总体假设是，衰老是创伤愈合的重要组成部分， 心具体地说，我们假设，在老年人心脏与愈合的MI，老化之间的相互作用， 心肌细胞（CM）具有较低的促凋亡活性阈值， 在老化心脏中观察到的这种反应可能会导致心肌梗死。此外，我们假设， 也通过影响衰老的动力学， 衰老细胞的内在特性，或它们被免疫系统清除。这种多PI 该提案汇集了几位具有非常不同专业知识的研究人员，以研究SCD的机制 在老化的心脏，使用一种新的年龄适当的大动物模型（兔），CFs特异性基因修饰 小鼠，以及CM和CF的工程化3D微组织，其中可以在体外研究它们的相互作用。在Aim中 Koren组将研究老化兔心脏中的梗死愈合过程，与 年轻的心脏，并与CMs和CFs的分子和细胞分析相关， 与远端区（RZ）相比，来自IBZ和梗死区（IZ）的肌成纤维细胞。在Aim 2中， Sedivy课题组将利用小鼠模型重点研究CFs在此过程中的衰老作用。衰老将是 使用遗传学和药理学方法在体内操作，将在体外培养和研究CF。 离体心脏的光学标测将用于研究心脏发生。在《目标3》中，门德和崔 小组将研究衰老的CFs对仿生中兴奋，传导和钙处理的影响。 心脏微组织，其中CM和衰老的CF可以通过直接的细胞-细胞接触相互作用。总之，我们 设想通过了解控制细胞衰老的衰老机制，我们将能够 减少纤维化和SCD的发病率。

Aging is associated with more than a 10-fold increase in the incidence of sudden cardiac death (SCD). Cellular senescence is a stress response that is characterized by an irreversible loss of proliferative capacity, accompanied by a complex senescence-associated secretory phenotype (SASP) that can have profound effects on neighboring cells in the tissue. Our research plan is based on the following main premises. First, that fibrosis is a consequence of heart injury (myocardial infarction) by being part of the natural wound healing response, and that inflammatory processes in the scar may predispose the heart to arrhythmias. Second, that cellular senescence of cardiac fibroblasts (CFs) plays an important role in post-MI wound healing. The overarching hypothesis of our proposal is that senescence is an important component of wound healing in the heart. Specifically, we postulate that in the aging human heart with a healed MI, the interplay between aging cardiomyocytes (CMs) that have a lower threshold for arrhythmogenic activity, and the a modified senescence response observed in the aging heart may lead to arrhythmogenesis. Furthermore, we hypothesize that aging also impacts the senescence of cardiac fibroblasts (CFs) by either affecting the kinetics of the senescence response, the intrinsic properties of the senescent cells, or their clearance by the immune system. This multi-PI proposal brings together several investigators with very different expertise to investigate mechanisms of SCD in the aging heart, using a novel age-appropriate large animal model (rabbit), CFs-specific genetically modified mice, and engineered 3D microtissues of CMs and CFs where their interactions can be studied in vitro. In Aim 1 the Koren group will investigate the infarct healing process in the aging rabbit heart, as compared to the young heart, and correlate the arrhythmogenesis with molecular and cellular analysis of CMs and CFs and myofibroblasts derived from the IBZ and infarct zone (IZ) as compared to the remote zone (RZ). In Aim 2 the Sedivy group will use mouse models to focus on the role CFs senescence in this process. Senescence will be manipulated in vivo using genetic and pharmacologic approaches, CFs will be cultured and investigated in vitro. Optical mapping of hearts ex vivo will be used to study arrhythmogenesis. In Aim 3 the Mende and Choi groups will study the effect of senescent CFs on excitation, conduction and calcium handling in biomimetic cardiac microtissues, in which CMs and senescent CFs can interact via direct cell-cell contact. In summary, we envision that by understanding the aging mechanisms that control cellular senescence we will be able to reduce fibrosis and the incidence of SCD.