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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.

项目总结