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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：
10219827
负责人：
THOMAS P. CAPPOLA
金额：
$ 79.5万
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/10219827
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.

项目概要心力衰竭是一种复杂且异质的综合征，给公众健康带来沉重负担。尽管对心肌细胞生物学基础研究进行了数十年的投资，但药物治疗仅针对心力衰竭的神经激素反应，并不直接针对肌细胞功能障碍。这因此，在了解肌细胞生物学方面的大量投资仍未转化为患者的利益。在动物模型中看似有希望的方法经常被证明在人类中无效主题，使人们对此类模型单独确定最引人注目的目标的相关性产生怀疑。非常大的群体样本中的基因组科学现已成熟到体内目标人类的相关性可以仅通过遗传关联直接确定。因此人类基因组学提供了目标选择的路线图以及模型系统和药物开发实验的重点。通过结合群体基因组学、转录组学和表观基因组学方法，我们发现令人信服的证据支持 MTSS1 作为人类心肌疾病的治疗靶点。在我们的初步研究，我们发现心脏特异性增强子内的遗传变异降低了表达 MTSS1 专门存在于左心室，并与人类多种心脏保护表型相关人群，包括左心室 (LV) 质量减少、左心室直径减少、分数增加缩短，并降低扩张型心肌病的风险。此外，我们还发现 Mtss1 敲除小鼠具有与人类研究结果相似的基线心脏表型（左心室质量、左心室尺寸和左心室尺寸减少）射血分数增加）。这些发现激发了我们的中心假设：MTSS1 的减少将对心肌疾病有保护作用。该提案的总体目标是（1）完善患者可能从 MTSS1 减少中获益最多的亚组，(2) 建立关联的因果关系降低 MTSS1 和心脏保护之间的关系，以及 (3) 调节体内心脏 MTSS1 表达以评估治疗效果和蛋白质生物学。