Modifying Factors and Phenotype Heterogeneity in Familial Hypertrophic Cardiomyopathy

家族性肥厚性心肌病（FHC）是一种以心肌异常增厚为特征的遗传性疾病，患者的临床症状从轻微症状到心力衰竭和猝死不等。在我们的社区中，FHC是35岁以下人群猝死的最常见原因，是由心脏细胞结构和功能中重要的基因（DNA）缺陷引起的。了解和确定DNA缺陷如何导致FHC临床特征的分子步骤是本项目研究的重点。在患有FHC的家庭中，一个常见的现象是在同一家庭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，而他或她的兄弟姐妹可能会出现严重的症状，心力衰竭，或者早期猝死。即使在具有相同遗传缺陷的个体之间，临床特征的这种差异的原因很可能反映了继发性修饰因素，例如遗传和/或环境因素，它们调节导致fhc的原发性基因缺陷的表达。本项目将重点识别和研究这些修饰因素。该项目的一个方面将集中于鉴定一种基因修饰剂，这种修饰剂已被证明存在于基因工程的FHC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，包括可能预防疾病进展的药理学因素、饮食因素（如咖啡因摄入）和生活方式因素（如运动）。通过这些研究，人们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，治疗并最终预防或治愈这种遗传性心脏疾病。

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.