MTSS1 in Myocardial Disease

项目摘要 心力衰竭是一种复杂的异质性综合征，给公共卫生带来了巨大负担。 尽管在心肌细胞生物学的基础研究上进行了数十年的投资， 靶向心力衰竭的神经激素反应，而不直接靶向肌细胞功能障碍。的 因此，在理解肌细胞生物学方面的大量投资仍未转化为患者的益处。 在动物模型中似乎有希望的方法在人类中经常被证明是无效的 这一问题使人怀疑仅凭这些模型就能确定最引人注目的目标是否合适。 在非常大的群体样本中的基因组科学现在已经成熟到这样的程度， 在人类中的相关性可以仅通过遗传关联直接确定。人类基因组学因此 为目标选择提供了路线图，并为模型系统和药物开发的实验提供了重点。 使用群体基因组学、转录组学和表观基因组学方法的组合，我们发现了 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 初步研究，我们发现心脏特异性增强子内的遗传变异减少了表达， MTSS1在左心室特异性表达并与多种心脏保护表型相关 人群，包括左心室（LV）质量减小、LV直径减小、分数增加 缩短和降低扩张型心肌病的风险。此外，我们发现Mts1基因敲除小鼠 具有与人类结果相似的基线心脏表型（LV质量、LV尺寸和 射血分数增加）。这些发现激发了我们的中心假设，即MTSS1的减少将是 对心肌疾病有心脏保护作用。该提案的总体目标是（1）完善患者 可能从MTSS1降低中获益最大的亚组，（2）确定相关性的因果关系 降低MTSS1和心脏保护之间的关系，和（3）调节体内心脏MTSS1表达以评估 治疗效果和蛋白质生物学。

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.