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

衰老与心脏性猝死(SCD)的发生率增加10倍以上有关。蜂窝 衰老是一种应激反应，其特征是增殖能力不可逆转地丧失， 伴随着复杂的衰老相关分泌表型(SASP)，可以有深刻的 对组织中邻近细胞的影响。我们的研究计划是基于以下主要前提的。第一，就是 纤维化是心脏损伤(心肌梗死)的结果，是伤口自然愈合的一部分。 疤痕中的炎症过程可能使心脏更容易发生心律失常。第二，就是 心肌成纤维细胞(CFs)的细胞衰老在心肌梗死后创面愈合中起重要作用。这个 我们建议的首要假设是衰老是创伤愈合的一个重要组成部分。 心。具体地说，我们假设，在有治愈的心肌梗塞的老化的人的心脏中，衰老之间的相互作用 具有较低的致心律失常活动阈值的心肌细胞(CM)，以及a修饰的衰老 在老化的心脏中观察到的反应可能会导致心律失常。此外，我们假设衰老 也通过影响衰老动力学影响心脏成纤维细胞(CFs)的衰老 反应，衰老细胞的固有属性，或免疫系统对它们的清除。这是多路PI Proposal汇集了几个具有非常不同专业知识的研究人员来研究SCD的机制 在老化的心脏中，使用一种新的适合年龄的大动物模型(兔)，CFS特异性基因修饰 小鼠，以及CMS和CFS的工程3D显微组织，它们之间的相互作用可以在体外进行研究。在AIM 1 Koren小组将研究老化兔心脏的梗塞愈合过程，与 并将心律失常的发生与CMS和CFS的分子和细胞分析相关联。 肌成纤维细胞来源于IBZ和梗死区(IZ)，而不是远区(RZ)。在目标2中， Sedivy课题组将利用小鼠模型重点研究CFS衰老在这一过程中的作用。衰老将是 使用遗传和药理学方法在体内操纵CFs，将在体外培养和研究CFs。 体外心脏光学标测将用于研究心律失常的发生。在《目标3》中，门德和崔 研究小组将研究衰老的CFS在仿生中对兴奋、传导和钙处理的影响 心脏微组织，在其中CMS和衰老的CFs可以通过直接的细胞-细胞接触相互作用。总而言之，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的发生率。

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.