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

• 批准号: 10438833
• 负责人: MICHELLE L MATTER
• 金额: $ 2.31万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-13 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10438833
• 关键词: Acute; Adenoviruses; Adhesions; Adult; Aminoacyl-tRNA hydrolase; Apoptosis; Attenuated; Automobile Driving; BCL2 gene; Birth; CASP3 gene; Calcium; Cardiac Myocytes; 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; human old age (65+); infancy; inhibitor; insight; knock-down; male; maternal morbidity; mortality; mouse model; mutant; peripartum cardiomyopathy; pre-clinical; pregnant; protein expression; response; targeted treatment; therapeutic target

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.

项目摘要 产后心肌病（PPCM）是一种病因不明的疾病， 无心脏病史的女性怀孕并发症。它发生在 1：1800至1：3500出生在美国，其特点是急性发作 在怀孕的最后一个月或产后五个月内发生心力衰竭。 PPCM是孕产妇发病率和死亡率的主要原因， 提供治疗选择。妊娠相关性肥大 启动心肌细胞保护信号通路的激活， 应激介导的凋亡。在PPCM患者中， 细胞凋亡导致不可逆的功能障碍和心力衰竭。蜂窝 驱动心肌细胞凋亡的机制尚未完全了解。我们有 鉴定了一个基因PTRH 2（也称为Bit-1），它在进化上是保守的，介导 整合素调节细胞存活和凋亡，该基因突变启动子 人类多系统疾病我们假设PTRH 2是必需的， 保护心脏免受母体心脏的围产期压力。为了研究这个问题， 开发了心肌细胞特异性PTRH 2缺失（CKO）。CKO男性，从不- 怀孕的雌性小鼠没有心脏缺陷，并且可以活到老年。然而，在这方面， 100%的CKO妊娠雌性小鼠以剂量依赖性方式发生PPCM (CKO>HET）。我们将使用细胞和分子生物学以及CKO小鼠来确定 PTRH 2如何介导心脏保护，测试PTRH 2相关蛋白是否 消除CKO妊娠小鼠中的PPCM表型，确定PTRH 2 表达阻断肥大，并检查PPCM患者心脏样品的PTRH 2 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存活途径，试验PTRH 2 在PPCM的临床前小鼠模型中的定向治疗策略，并确定 PTRH 2突变是否促进PPCM。