Placental Senescence in Peripartum Cardiomyopathy

围产期心肌病中的胎盘衰老

• 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
• 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

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.

项目总结/摘要 围产期心肌病（PPCM）是一种罕见的心力衰竭（HF），发生在女性晚期， 怀孕到产后早期。虽然PPCM的发病率正在增加，但这种综合征的病因 仍然不清楚，可用的治疗方法有限。一种“两次打击”机制-其中1）一种未被识别的遗传基因 HF的易感性被2）妊娠晚期有害循环因子的激增所掩盖-是 PPCM中的主要假设。我们对PPCM理解的一个根本性差距是核心病理学 驾驶这“第二击”是。我们的研究小组最近分析了PPCM或先兆子痫妇女的循环蛋白质组 （一个主要的PPCM风险因素），以深入了解他们共同的分泌病理生理学。这一矛盾的 确定了衰老相关的分泌表型（SASP），生物衰老的标志，作为最 在这些年轻女性中高度上调的生物过程。我们在人类队列中的初步数据， 实验模型已经确定了衰老生物学和心功能障碍之间的密切联系 和HF严重程度，并最终导致我们提出一个新的假设，即加速胎盘衰老是 PPCM病理生理学中“第二次打击”的难以捉摸的根本原因。胎盘的寿命被限制在40岁左右 周，可以被视为人体中老化最快的器官，并且明显地变得明显衰老 怀孕后期。我们的目的是证明PPCM胎盘衰老的因果关系。在这里我们建议 三个集成的特定目标，包括严格的增益和功能损失实验，以明确 回答问题.在目标1中，我们将使用联体共生和异位胎盘植入来确定 衰老的胎盘分泌物组足以诱导PPCM易感小鼠的心功能障碍。在目标2中，我们将 结合药理学和遗传衰老方法，以确定胎盘衰老是否 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源性 衰老相关分泌因子诱导病理性心肌细胞肥大，独立于 血流动力学效应。这将整合全面的功能，结构和代谢表型， 在人心肌细胞-胎盘串扰的离体模型系统中的蛋白质组学和RNAseq probling。我们 这种方法结合了创新的假设，最先进的技术和独特的实验策略。的 拟议的研究是重要的，因为它预计将提供重要的新的机制见解，这一点 对HF综合征知之甚少，这可能从根本上改变我们研究心脏病的框架。 妊娠期重塑这项工作的翻译潜力突出了我们对分泌蛋白的关注 可以作为治疗开发的靶点，并可能与更广泛的HF相关 与衰老相关的综合征（如衰老、癌症）。鉴于我们小组在衰老生物学方面的专业知识， 心血管生理学和HF的实验模型，沿着我们的合作者的专业知识， PPCM，先兆子痫和人类基因组学，我们有能力完成拟议的研究。