Placental Senescence in Peripartum Cardiomyopathy

围产期心肌病中的胎盘衰老

基本信息

批准号：
10716493
负责人：
JASON DAVID ROH
金额：
$ 47.63万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10716493
关键词：
Acceleration Aging Automobile Driving Biological Biological Aging Biological Markers Biological Models Biological Process Biology Biology of Aging Cardiac Cardiac Myocytes Cardiovascular Diseases Cardiovascular Physiology Cells Clinical Coculture Techniques Data Development Disease Etiology Experimental Models Functional disorder Genetic Genetic Predisposition to Disease Health Heart Heart Diseases Heart failure Human Human body Hypertrophy Incidence Individual Infection Intervention Late pregnancy Longevity Malignant Neoplasms Metabolic Mission Modeling Mus Myocardial dysfunction National Heart, Lung, and Blood Institute Organ Parabiosis Pathogenesis Pathologic Pathway interactions Phenotype Placenta Postpartum Period Pre-Clinical Model Pre-Eclampsia Pregnancy Process Proteins Proteome Proteomics Public Health Research Risk Factors Role Serum Severities Study models Syndrome System Technology Therapeutic Tissues United States National Institutes of Health Ventricular Remodeling Woman Work activin A case control cohort experimental study gain of function heart function hemodynamics human genomics implantation improved in vitro Model in vivo innovation insight loss of function metabolic phenotype novel paracrine peripartum cardiomyopathy pharmacologic research study secretory protein senescence targeted treatment therapeutic development transcriptome sequencing translational potential young woman

项目摘要

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.

项目概要/摘要围产期心肌病 (PPCM) 是一种罕见的心力衰竭 (HF)，发生于女性产后晚期。尽管 PPCM 的发病率正在增加，但该综合征的病因仍不清楚。仍不清楚，可用的治疗方法有限——其中 1) 未被识别的遗传。 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——是 PPCM 的主要假设是我们对 PPCM 理解的一个根本差距是核心病理学。推动这一“第二次打击”的是我们的小组最近对患有 PPCM 或先兆子痫的女性的循环蛋白质组进行了分析。（一个主要的 PPCM 风险因素）来深入了解他们共同的分泌病理生理学。确定了衰老相关的分泌表型（SASP），这是生物衰老的标志，是最重要的我们在人类队列中的初步数据和这些年轻女性的生物过程高度上调。实验模型已确定衰老生物学与心脏功能障碍之间的密切关联和 PPCM 中的 HF 严重程度，并最终使我们得出一个新的假设：加速胎盘衰老是 PPCM 病理生理学中“第二次打击”的难以捉摸的根本原因是胎盘，其寿命仅限于 40 岁左右。几周，可以被视为人体衰老最快的器官，并且明显衰老我们的目标是证明 PPCM 中胎盘衰老的因果关系。三个综合的具体目标，其中结合了严格的功能获得和丧失实验，以明确在目标 1 中，我们将使用联体共生和异位胎盘植入来回答这个问题。在目标 2 中，衰老胎盘分泌组足以诱发 PPCM 小鼠的心脏功能障碍。结合药理学和遗传衰老方法来确定胎盘衰老是否与最后，在目标 3 中，我们将系统地鉴定新型胎盘来源。衰老相关的分泌因子可诱导病理性心肌细胞肥大，独立于这将整合全面的功能、结构和代谢表型。人类心肌细胞-胎盘串扰的离体模型系统中的蛋白质组学和 RNAseq 分析。该方法结合了创新假设、最先进的技术和独特的实验策略。拟议的研究意义重大，因为预计它将为此提供重要的新机制见解人们对心衰综合征知之甚少，它可能从根本上改变我们处理心脏病的框架我们对分泌蛋白的关注凸显了这项工作的转化潜力。可以作为治疗开发的目标，并且可能与更广泛的心力衰竭相关鉴于我们团队在衰老生物学方面的专业知识，与衰老相关的综合征（例如衰老、癌症）。心血管生理学、心力衰竭实验模型，以及我们合作者在以下方面的专业知识 PPCM、先兆子痫和人类基因组学，我们有能力完成拟议的研究。