Functional Validation of Myh14 in Stress-Induced Cardiac Remodeling.

项目总结/摘要 心力衰竭是住院的主要原因，也是医疗保健不断增长的主要驱动力之一 成本，是一种复杂的疾病，是多种基因相互作用的结果，结合生活方式 和环境因素。以前的大规模人类全基因组关联研究，以确定遗传 潜在的心力衰竭疾病谱的变异产生了有限的见解。作为我博士论文的一部分， 我们求助于一个系统遗传学资源，称为杂交小鼠多样性小组， 慢性异丙肾上腺素应激3周后的结构和功能变化。我们发现Myh 14是一种 最有可能是左心室肥大使用基因修饰的Myh 14敲除小鼠系， 我们证实Myh 14是慢性异丙肾上腺素致左心室肥厚的一种新的修饰基因 刺激. 该提案描述了一个为期五年的指导医生-科学家培训计划，以进一步确定 Myh 14在应激诱导的心脏重塑中的作用我们假设Myh 14是一个负调节因子， 肥厚基于使用系统遗传学和实验发现的优先级，我们概述了一个 一系列分子生物学、细胞生物学和小鼠遗传学方法来测试Myh 14缺陷是否 导致肥大、Wnt/β-连环蛋白和FOXO 1信号传导的改变。该研究将提供 Myh 14如何调节应激诱导的心脏重塑的基本见解， 了解常见的遗传变异如何在应激诱导的心脏重塑中发挥作用。 概述的程序将允许候选人发展在新的功能验证的掌握 利用分子生物学、细胞生物学和小鼠遗传学技术研究心脏重塑的候选基因 这是一个长期的目标，即了解遗传变异如何改变人类的心血管疾病。 密集的研究计划将允许候选人开始这个研究项目，同时具有 为实现成长为独立调查员的目标，需要提供必要的指导和支持。的 本项目的目标与NIH和NHLBI的主要战略目标一致，以提高我们对以下问题的理解： 健康和疾病的分子和生理基础。

PROJECT SUMMARY / ABSTRACT Heart failure, a leading cause of hospitalization and one of the primary driving forces behind rising healthcare costs, is a complex disease that is a result of the interplay among multiple genes in combination with lifestyle and environmental factors. Previous large-scale human genome-wide association studies to identify genetic variation underlying the heart failure disease spectrum have yielded limited insights. As part of my PhD thesis, we turned to a systems genetics resource, called the Hybrid Mouse Diversity Panel, to characterize cardiac structural and functional changes under chronic isoproterenol stress over 3 weeks. We identified Myh14 as a top candidate for left ventricular mass hypertrophy. Using a genetically modified Myh14 knockout mouse line, we validated Myh14 as a novel modifier gene for left ventricular hypertrophy secondary to chronic isoproterenol stimulation. This proposal describes a five-year mentored physician-scientist training program to further define the role of Myh14 in stress-induced cardiac remodeling. We hypothesize that Myh14 is a negative regulator of hypertrophy. Based on prioritization using systems genetics and experimental findings, we have outlined a series of molecular biology, cell biology, and mouse genetics approaches to test whether Myh14 deficiency leads to alteration in hypertrophic, Wnt/β-catenin and FOXO1 signaling. The proposed research will provide fundamental insights into how Myh14 modulates stress-induced cardiac remodeling and open a new understanding of how common genetic variation plays a role in stress-induced cardiac remodeling. The outlined program will allow the candidate to develop a mastery in the functional validation of novel candidate genes in cardiac remodeling using molecular biology, cell biology and mouse genetics techniques towards the long-term goal of understanding how genetic variation modifies cardiovascular disease in humans. The intensive research plan will allow the candidate to embark upon this research project, while having the necessary mentorship and support needed towards the goal of maturing into an independent investigator. The aims of this project are aligned with the major strategic goal of NIH and NHLBI to improve our understanding of the molecular and physiologic basis of health and disease.