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：
10192771
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/10192771
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/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.

项目摘要产后心肌病（PPCM）是一种未知病因的疾病，如没有心脏病的女性怀孕并发症。它发生在 1：1800至1：3500在美国的出生，以急性发作为特征在怀孕的最后一个月或产后五个月内心力衰竭。 PPCM是孕产妇发病率和死亡率的主要原因，没有PPCM特异性可用的治疗选择。怀孕期间，妊娠相关肥大启动心肌细胞保护性信号通路的激活应力介导的凋亡。在PPCM患者中，心肌细胞有所增加导致不可逆的功能障碍和心力衰竭的凋亡。细胞驾驶心肌细胞凋亡的机制尚不完全了解。我们有鉴定出一个在进化上保守的基因PTRH2（也称为BIT-1），介导整联蛋白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对于孕产妇心脏的围绕围胁迫的心脏保护。为了研究这个我们开发了PTRH2（CKO）的心肌细胞特异性缺失。 CKO男性，从未 - 怀孕的雌性小鼠没有心脏缺陷，并且活到老年。然而， 100％的CKO怀孕雌性小鼠以剂量依赖性的方式发展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，测试PTRH2是否相关蛋白废除CKO怀孕小鼠中的PPCM表型，确定PTRH2是否表达阻塞肥大并检查PPRH2的PPCM患者心脏样本基因突变。拟议的项目有可能确定重要的在妊娠相关肥大，测试PTRH2中激活的生存途径在PPCM的临床前小鼠模型中定向治疗策略，并确定 PTRH2中的突变是否促进PPCM。