Placental Senescence in Peripartum Cardiomyopathy
Funded Grant
Overview
Affiliation
View All
Overview
description
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.
