Placental Senescence in Peripartum Cardiomyopathy

项目摘要/摘要 围产期心肌病(PPCM)是一种罕见的心力衰竭(HF)形式，发生在晚期妇女 妊娠至产后早期。虽然PPCM的发病率在增加，但这种综合征的病因 目前仍不清楚，可用的治疗方法有限。一种“两击”机制--其中1)一种未被识别的基因 2)妊娠晚期有害循环因子的激增揭示了心力衰竭的易感性--这是 PPCM中的领先假设。我们对PPCM理解的一个根本差距是什么是核心病理生物学 驾驶这首《第二支金曲》是。我们小组最近对患有子痫前期或子痫前期的妇女的循环蛋白质组进行了分析 (PPCM的一个主要风险因素)，以深入了解他们共同的分泌病理生理学。这是自相矛盾的 发现衰老相关分泌表型(SASP)是最常见的生物衰老的标志 这些年轻女性体内的生物过程被高度上调。我们人类队列的初步数据和 实验模型已经确定了衰老生物学和心脏功能障碍之间的强烈联系 和PPCM中心衰的严重性，并最终引导我们提出了一个新的假设，即加速胎盘衰老是 PPCM病理生理学中“二次打击”的难以捉摸的根本原因。胎盘，其寿命被限制在40岁左右 几周后，可以被视为人体衰老最快的器官，特别是会明显衰老 到怀孕后期。我们的目标是证明PPCM中胎盘衰老的因果关系。在这里，我们建议 三个综合的具体目标，包括严格的功能增减实验，以明确 回答这个问题。在目标1中，我们将使用异体共生和异位胎盘植入来确定 衰老的胎盘分泌体足以引起PPCM倾向小鼠的心功能障碍。在目标2中，我们将 结合药理学和遗传衰老方法来确定胎盘衰老是否 在PPCM病理生理学中是必要的。最后，在目标3中，我们将系统地鉴定新的胎盘来源 诱导病理性心肌细胞肥大的衰老相关分泌因子，不依赖于 血液动力学效应。这将把全面的功能、结构和代谢表型与 蛋白质组学和RNAseq在人心肌细胞-胎盘串扰体外模型系统中的研究。我们的 方法结合了创新的假设、最先进的技术和独特的实验策略。这个 提出的研究具有重要意义，因为它有望为这一问题提供重要的新的机械论见解 知之甚少的心衰综合征，可能会从根本上改变我们处理心脏疾病的框架 妊娠期间的重塑。我们对分泌蛋白质的关注突出了这项工作的翻译潜力。 这可以作为治疗开发的靶点，并可能与更广泛的HF谱相关 与衰老相关的症状(如衰老、癌症)。鉴于我们团队在衰老生物学方面的专业知识， 心血管生理学和心力衰竭的实验模型，以及我们的合作者在 PPCM、先兆子痫和人类基因组学，我们完全有能力完成这项拟议的研究。

PROJECT SUMMARY/ABSTRACT Peripartum cardiomyopathy (PPCM) is a rare form of heart failure (HF) that occurs in women during late pregnancy to the early postpartum period. Although PPCM incidence is increasing, the etiology of this syndrome remains unclear and limited treatments are available. A “2-hit” mechanism— in which 1) an unrecognized genetic predisposition for HF is unmasked by 2) a surge of deleterious circulating factors in late pregnancy—is the leading hypothesis in PPCM. A fundamental gap in our understanding of PPCM is what the core pathobiology driving this “2nd hit” is. Our group recently profiled the circulating proteome of women with PPCM or preeclampsia (a major PPCM risk factor) to gain insights into their shared secretory pathophysiology. This paradoxically identified the senescence-associated secretory phenotype (SASP), a marker of biological aging, as the most highly upregulated biological process in these young women. Our preliminary data in human cohorts and experimental models has identified strong associations between senescence biology and cardiac dysfunction and HF severity in PPCM, and ultimately led us to a novel hypothesis that accelerated placental senescence is the elusive root cause of the “2nd hit” in PPCM pathophysiology. The placenta, whose lifespan is limited to ~40 weeks, can be viewed as the fastest aging organ in the human body and notably becomes markedly senescent by late pregnancy. Our objective here is to prove causality of placental senescence in PPCM. Here we propose three integrated Specific Aims that incorporate rigorous gain- and loss-of-function experiments to definitively answer this question. In Aim 1, we will use parabiosis and heterotopic placental implantation to determine if the senescent placenta secretome is sufficient to induce cardiac dysfunction in PPCM-prone mice. In Aim 2, we will incorporate pharmacological and genetic senolytic approaches to determine if placental senescence is necessary in PPCM pathophysiology. Lastly, in Aim 3, we will systematically identify novel placenta-derived senescence-associated secretory factors that induce pathologic cardiomyocyte hypertrophy, independent of hemodynamic effects. This will integrate comprehensive functional, structural, and metabolic phenotyping with proteomic and RNAseq profling in an ex vivo model system of human cardiomyocyte-placental crosstalk. Our approach combines innovative hypotheses, state-of-the-art technology, and unique experimental strategies. The proposed research is significant because it is expected to provide important new mechanistic insights into this poorly understood HF syndrome that could fundamentally change the framework by which we approach cardiac remodeling in pregnancy. The translational potential of this work is highlighted by our focus on secretory proteins that can be targeted for therapeutic development, and could potentially be relevant to a broader spectrum of HF syndromes associated with senescence (e.g. aging, cancer). Given our group’s expertise in aging biology, cardiovascular physiology, and experimental models of HF, along with the expertise of our collaborators in PPCM, preeclampsia, and human genomics, we are well equipped to complete the proposed research study.