Modifying Factors and Phenotype Heterogeneity in Familial Hypertrophic Cardiomyopathy

家族性肥厚型心肌病的修饰因素和表型异质性

• 批准号: nhmrc : 227100
• 负责人: Prof Christopher Semsarian
• 金额: $ 26.3万
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2003
• 资助国家: 澳大利亚
• 起止时间: 2003-01-01 至 2005-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/modifying-factors-phenotype-hypertrophic-cardiomyopathy/97086
• 关键词: Modifying; Factors; Phenotype; Heterogeneity; Familial

Familial Hypertrophic Cardiomyopathy (FHC) is an inherited disorder characterised by abnormal thickening of heart muscle, resulting in clinical symptoms in affected individuals ranging from mild symptoms, to heart failure and sudden death. FHC is the commonest cause of sudden death in individuals aged less than 35 yrs in our community, and is caused by defects in genes (DNA) important in the heart's cellular structure and function. Understanding and identifying the molecular steps involved in how this defect in our DNA can lead to the clinical features of FHC, is the focus of the research described in this project. A common occurrence in families with FHC is the identification of two affected individuals within the same family (e.g. siblings) and who therefore have the same genetic defect, with variable clinical outcomes. For example, one sibling may have no symptoms and live a normal life, while his-her sibling, may develop severe symptoms, heart failure, and-or early sudden death. The reason for such diversity in clinical features, even amongst individuals with the same genetic defect, most likely reflects secondary modifying factors, e.g. genetic and-or environmental factors which modulate the expression of the primary FHC-causing gene defect. This project will focus on identifying and studying such modifying factors. One aspect of the project will focus on the identification of a genetic modifier which has been shown to exist in a genetically-engineered mouse model of FHC. A second aspect of the proposed research will focus on potential environmental factors, including pharmacological agents which may prevent disease progression, dietary factors, e.g. caffeine intake, and lifestyle factors , e.g. exercise. Through these studies, it is hoped that key molecules and important pathogenic mechanisms will be identified, leading to the development of potentially new therapies, to both treat, and ultimately prevent or cure this inherited cardiac disorder.

家族性肥厚性心肌病（FHC）是一种遗传性疾病，其特征是心肌异常增厚，导致受影响个体的临床症状从轻度症状到心力衰竭和猝死。FHC是我们社区中年龄小于35岁的人猝死的最常见原因，并且是由心脏细胞结构和功能中重要的基因（DNA）缺陷引起的。理解和识别我们DNA中的这种缺陷如何导致FHC临床特征的分子步骤，是本项目所述研究的重点。FHC家族中常见的情况是在同一家族中发现两个受影响的个体（例如兄弟姐妹），因此他们具有相同的遗传缺陷，临床结果不同。例如，一个兄弟姐妹可能没有任何症状，过着正常的生活，而他的兄弟姐妹可能会出现严重的症状，心力衰竭，和-或早期猝死。即使在具有相同遗传缺陷的个体中，临床特征的这种多样性的原因也很可能反映了次级修饰因子，例如调节引起原发性FHC的基因缺陷的表达的遗传和/或环境因子。本项目将侧重于确定和研究这些修改因素。该项目的一个方面将集中在鉴定一种遗传修饰剂，该修饰剂已被证明存在于FHC的基因工程小鼠模型中。拟议研究的第二个方面将侧重于潜在的环境因素，包括可能防止疾病进展的药物，饮食因素，如咖啡因摄入量，以及生活方式因素，如运动。通过这些研究，希望能够确定关键分子和重要的致病机制，从而开发出潜在的新疗法，以治疗并最终预防或治愈这种遗传性心脏病。