CARDIAC STRUCTURE AND FUNCTURE IN BETA MYOSIN HEAVY CHAIN MISSENSE MUTATIONS

β 肌球蛋白重链错义突变的心脏结构和功能

• 批准号: 5214196
• 负责人: JONATHAN G SEIDMAN
• 金额: --
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5214196
• 关键词: heart failure; myosins; point mutation; protein engineering

We propose to study heart failure in beta cardiac MHC gene missense mutations. Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominantly inherited disorder of heart muscle. Individuals with FHC- causing mutations develop cardiac hypertrophy and myocyte disarray and are at significantly increased risk of heart failure and/or sudden death. About 40% of individuals with FHC have missense mutations in their beta cardiac MHC gene. A broad spectrum of clinical symptoms is found among individuals with the same beta cardiac MHC mutation. However, some beta cardiac MHC mutations are associated with high morbidity and mortality whereas others appear to have a more modest effect on life expectancy. Under the auspices of this grant we will use homologous recombination to produce mouse models of FHC. These murine models will enable us to further define the biologic consequences of specific mutations on cardiac structure and function. We will assess the role of other factors (both genetic and environmental) that modulate the hypertrophic phenotype. These animal models will also be invaluable for assessing energetics of the pre- symptomatic and symptomatic hypertrophic myocardium as well as providing tissue reagents for analyses of signal transduction pathways that may be perturbed in heart failure. Analyses of these mice will be greatly facilitated by our association with the SCOR. In particular, the progress and experience obtained in Projects 1, 3 and 4 of the SCOR in characterizing murine cardiac function will be necessary for our studies of mice bearing myosin mutations. Specifically we propose to: 1) Create mice bearing FHC-causing mutations by homologous recombination. 2) Define the effects of myosin mutations on cardiac development and structure. 3) Define and compare the phenotypes associated with each mutation, specifically to assess energetics and signal transduction pathways of genetically altered myocardium. 4) Assess the role of genetic background on the phenotypes associated with each mutation; to vary environmental factors (i.e. hormones, diet and exercise) and assess the effects on the pathophysiologic process. The creation of a genetic murine model of FHC will eventually allow us to take rational approaches to the development of pharmacologic therapies and behavioral modification that should benefit individuals with FHC. Ultimately, these studies will improve therapy of hypertrophy from many etiologies and may prevent heart failure.

我们建议研究β心脏MHC基因错过的心力衰竭 突变。 家族性肥厚性心肌病（FHC）是常染色体 心肌遗传的主要遗传障碍。 患有FHC-的个人 导致突变发生心脏肥大和肌细胞混乱，并且是 大大增加了心力衰竭和/或猝死的风险。 大约40％的FHC患者的beta中有错义突变 心脏MHC基因。 在中发现了广泛的临床症状 具有相同β心脏MHC突变的个体。 但是，一些Beta 心脏MHC突变与高发病率和死亡率有关 而其他人似乎对预期寿命产生了更大的影响。 在这笔赠款的主持下，我们将使用同源重组 产生FHC的小鼠模型。 这些鼠模型将使我们能够进一步 定义特异性突变对心脏结构的生物学后果 和功能。 我们将评估其他因素的作用（遗传和 环境）调节肥厚表型。 这些动物 模型对于评估前的能量学也将是无价的 有症状和有症状的肥厚心肌以及提供 组织试剂，用于分析可能是信号转导途径的 心力衰竭受到干扰。 这些小鼠的分析将是极大的 由我们与SCOR的关联促进。 特别是进步 以及在SCOR的项目1、3和4中获得的经验 对于我们的研究，需要表征鼠心脏功能 带有肌球蛋白突变的小鼠。 具体我们建议：1）创建鼠标 通过同源重组产生FHC引起的突变。 2）定义 肌球蛋白突变对心脏发育和结构的影响。 3） 定义和比较与每个突变相关的表型， 专门用于评估能量和信号转导途径 遗传改变心肌。 4）评估遗传背景的作用 在与每个突变相关的表型上；改变环境 因素（即激素，饮食和运动），并评估对 病理生理过程。 FHC的遗传鼠模型的创建 最终将使我们采取合理的方法来发展 药理学疗法和行为修改应受益 患有FHC的人。 最终，这些研究将改善 来自许多病因的肥大，可能预防心力衰竭。