MTSS1 in Myocardial Disease

项目总结 心力衰竭是一种复杂而多样的综合征，给公众健康带来了巨大的负担。 尽管几十年来对心肌细胞生物学的基础研究进行了投资，但药物疗法仅限于 针对心力衰竭的神经激素反应，而不直接针对心肌细胞功能障碍。这个 因此，在了解心肌细胞生物学方面的大量投资仍然没有转化为患者的利益。 在动物模型中似乎很有希望的方法在人类身上往往被证明是无效的 受试者，使人怀疑这些模型本身是否与确定最引人注目的目标有关。 在非常大的人群样本中的基因组科学现在已经成熟到了体内靶标的程度 仅通过基因关联就可以直接确定人类的相关性。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中的实验提供了重点。 使用群体基因组、转录组和表观基因组学方法的组合，我们已经发现 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 初步研究发现，心脏特异性增强子中的基因变异会减少表达 MTSS1基因在人左心室中的表达及其与多种心脏保护表型的相关性 人群，包括左心室(LV)质量减少，LV内径减少，分数增加 缩短，降低扩张型心肌病的风险。此外，我们还发现Mtss1基因敲除小鼠 有与人类相似的基线心脏表型(减少的左心室质量、左心室内径和 射血分数增加)。这些发现激发了我们的核心假设，即MTSS1的减少将是 对心肌疾病的心脏保护作用。这项建议的总体目标是(1)完善患者 可能从MTSS1削减中受益最大的子组(S)，(2)建立关联的因果关系 降低MTSS1与心脏保护之间的关系，以及(3)调节体内心脏MTSS1的表达以评估 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.