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MTSS1 in Myocardial Disease

MTSS1 在心肌疾病中的作用

基本信息

批准号：
9973229
负责人：
THOMAS P. CAPPOLA
金额：
$ 78.99万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-15 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9973229
关键词：
Adrenergic beta-Agonists Alleles Animal Model Attenuated Basic Science Biological Models Biology CRISPR/Cas technology Caliber Cardiac Cardiac Myocytes Cardiomyopathies Complex Coronary Arteriosclerosis DNA Development Dilated Cardiomyopathy Dimensions Disease Dyslipidemias EFRAC Enhancers Etiology Functional disorder Gene Expression Genes Genomics Goals Heart Heart failure Human Investments Knock-out Knockout Mice LDL Cholesterol Lipoproteins Left Left Ventricular Mass Left ventricular structure Low Density Lipoprotein Receptor Mediating Medicine Modeling Mus Muscle Cells Myocardial Infarction Myocardial Ischemia Outcome Pathogenicity Pathologic Patients Pharmacotherapy Phenotype Population Public Health Risk Sampling Subgroup Syndrome Systems Development Testing Therapeutic Therapeutic Effect Therapeutic Uses Transgenes Uncertainty Variant Ventricular biobank cardioprotection cohort constriction drug development epigenomics experimental study genetic association genetic variant genome sciences genomic data human genomics human subject improved in vivo induced pluripotent stem cell inhibitor/antagonist loss of function mouse model patient subsets preservation programs protein protein interaction receptor recycling response small hairpin RNA therapeutic protein therapeutic target transcriptomics

项目摘要

PROJECT SUMMARY Heart failure is a complex and heterogeneous syndrome that imposes a substantial burden on public health. Despite decades of investment in basic research in cardiomyocyte biology, pharmacotherapy exclusively targets the neurohormonal response to heart failure and does not directly target myocyte dysfunction. The substantial investment in understanding myocyte biology thus remains untranslated to patient benefit. Approaches that have appeared promising in animal models have frequently proven ineffective in human subjects, casting doubt on the relevance of such models alone to identify the most compelling targets. Genome science in very large population samples has now matured to the point where targets of in vivo relevance in humans can be identified directly through genetic association alone. Human genomics thus provides a roadmap for target selection and a focus for experiments in model systems and drug development. Using a combination of population genomic, transcriptomic, and epigenomic approaches, we have uncovered compelling evidence supporting MTSS1 as a therapeutic target for human myocardial disease. In our preliminary studies, we have found that genetic variants within a cardiac-specific enhancer reduce expression of MTSS1 specifically in the left ventricle and associate with multiple cardioprotective phenotypes in human populations, including reduced left ventricular (LV) mass, reduced LV diameter, increased fractional shortening, and reduced risk of dilated cardiomyopathy. Further, we have found that Mtss1 knockout mice have a baseline cardiac phenotype that parallels findings in humans (reduced LV mass, LV dimension, and increased ejection fraction). These findings motivate our central hypothesis that reduction of MTSS1 will be cardioprotective for myocardial diseases. The overall goals of this proposal are to (1) refine the patient subgroup(s) that might benefit the most from MTSS1 reduction, (2) establish causality of the association between reduced MTSS1 and cardioprotection, and (3) modulate cardiac MTSS1 expression in vivo to assess therapeutic effects and protein biology.

项目总结