Protecting the Maternal Heart From Pregnancy-Associated Heart Disease

保护母亲心脏免受妊娠相关心脏病的影响

基本信息

批准号：
9762134
负责人：
MICHELLE L MATTER
金额：
$ 38.5万
依托单位：
UNIVERSITY OF HAWAII AT MANOA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-13 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9762134
关键词：
Acute Adenoviruses Adhesions Adult Age Aminoacyl-tRNA hydrolase Apoptosis Attenuated Automobile Driving BCL2 gene Birth CASP3 gene Calcium Cardiac Myocytes Cardiomyopathies Cell Death Cell Survival Cells Cellular Stress Cellular biology Chronic Data Defense Mechanisms Disease Dose Etiology Family Female Functional disorder Gene Mutation Genes Genetic Transcription Heart Heart Abnormalities Heart Diseases Heart failure Human Hypertrophy In Vitro Integrins Knockout Mice Life MCL1 gene Maternal Mortality Mechanical Stress Mechanics Mediating Mitochondria Molecular Molecular Biology Morbidity - disease rate Mus Mutation Myosin ATPase Myosin Heavy Chains Normal Cell Oxidative Stress PI3K/AKT Pathogenesis Pathogenicity Pathway interactions Patients Perinatal Periodicity Persons Phenotype Play Postpartum Period Pre-Clinical Model Pregnancy Pregnancy Complications Pregnant Women Proteins Rattus Reporting Risk Role Sampling Signal Pathway Signal Transduction Stress Stretching Testing Therapeutic United States Vascular Endothelial Growth Factors Woman Work cardioprotection infancy inhibitor/antagonist insight knock-down male maternal morbidity mortality mouse model mutant peripartum cardiomyopathy pre-clinical pregnant protein expression response targeted treatment therapeutic target

项目摘要

Project Summary Postpartum cardiomyopathy (PPCM) is a disease of unknown etiology that arises as a complication of pregnancy in women with no prior heart disease. It occurs in 1:1800 to 1:3500 births in the United States and is characterized by an acute onset of heart failure during the last month of pregnancy or within five months postpartum. PPCM is a major cause of maternal morbidity and mortality with no PPCM-specific treatment options available. During pregnancy, pregnancy-associated hypertrophy initiates the activation of cardiomyocyte protective signaling pathways that block stress-mediated apoptosis. In PPCM patients there is an increase in cardiomyocyte apoptosis that leads to irreversible dysfunction and heart failure. The cellular mechanisms driving cardiomyocyte apoptosis are not fully understood. We have identified a gene PTRH2 (also called Bit-1) that is evolutionarily conserved, mediates integrin regulated cell survival and apoptosis, and mutations in this gene promote multisystem disease in humans. We hypothesize that PTRH2 is essential for cardioprotection from peripartum stresses in the maternal heart. To study this we developed a cardiomyocyte-specific deletion of PTRH2 (CKO). CKO male and never- pregnant female mice demonstrate no heart defects and live to old age. However, 100% of CKO pregnant female mice develop PPCM in a dose-dependent manner (CKO>HET). We will use cell and molecular biology and our CKO mice to determine how PTRH2 mediates cardioprotection, test whether PTRH2 associated proteins abrogate the PPCM phenotype in CKO pregnant mice, determine whether PTRH2 expression blocks hypertrophy and examine PPCM patient heart samples for PTRH2 gene mutations. The proposed project has the potential to identify an essential survival pathway that is activated in pregnancy-associated hypertrophy, test PTRH2 directed therapeutic strategies in a preclinical mouse model of PPCM and determine whether mutations in PTRH2 promote PPCM.

项目概要产后心肌病 (PPCM) 是一种病因不明的疾病，发生于既往没有心脏病的女性的一种妊娠并发症。它发生在美国出生率为 1:1800 至 1:3500，特点是急性发作妊娠最后一个月或产后五个月内发生心力衰竭。 PPCM 是孕产妇发病和死亡的主要原因，没有 PPCM 特异性可用的治疗方案。怀孕期间，妊娠相关肥大启动心肌细胞保护信号通路的激活，从而阻断应激介导的细胞凋亡。 PPCM 患者心肌细胞增多细胞凋亡导致不可逆的功能障碍和心力衰竭。蜂窝式驱动心肌细胞凋亡的机制尚不完全清楚。我们有鉴定出一个基因 PTRH2（也称为 Bit-1），该基因在进化上保守，介导整合素调节细胞存活和凋亡，该基因的突变促进人类多系统疾病。我们假设 PTRH2 对于保护母亲免受围产期应激的心脏保护。为了研究这个我们开发了一种心肌细胞特异性的 PTRH2 缺失（CKO）。 CKO 男且从不- 怀孕的雌性小鼠没有表现出心脏缺陷并且可以活到老年。然而， 100% 的 CKO 怀孕雌性小鼠以剂量依赖性方式发展 PPCM （CKO>HET）。我们将使用细胞和分子生物学以及我们的 CKO 小鼠来确定 PTRH2如何介导心脏保护作用，测试PTRH2是否相关蛋白消除CKO妊娠小鼠的PPCM表型，确定PTRH2是否存在表达阻断肥厚并检查 PPCM 患者心脏样本中的 PTRH2 基因突变。拟议的项目有可能确定一个重要的妊娠相关肥大中激活的生存途径，测试 PTRH2 在 PPCM 临床前小鼠模型中制定定向治疗策略并确定 PTRH2 突变是否会促进 PPCM。