Identification of genetics modifiers of heart diease

描述（由申请人提供）：心力衰竭是世界范围内死亡的重要原因，有许多心脏病因，包括心肌病引起的收缩功能障碍。然而，由于人群中未发现的遗传差异，心肌病的预后在患者之间变化很大。识别导致这些可变结果的遗传风险因素几乎对所有方法都是困难的，除了分析因明显的生物学合理性而选择的候选基因。我们的项目将在小鼠中使用无偏倚的遗传作图方法来识别调节心肌病进展和结果的新基因。在一种经过充分研究的扩张型心肌病小鼠模型（Calsequestrin转基因小鼠）中，我们发现了疾病进展和生存的显著品系特异性差异。在多个杂交中使用QTL定位方法，我们已经确定了七个不同的遗传位点，Hrtfm1-7（心力衰竭修饰因子），可以改变疾病的进展。目前正在同源系中分离这些基因座。目的1：我们将在两种不同的心肌病背景下对分离的修饰基因座进行表型验证；(1)使用原始的CSQ转基因作为遗传增敏剂；(2)使用主动脉收缩引起的压力过载作为手术增敏剂。在两种模型中表现出稳健效应的分离基因座将得到进一步研究的优先权。目标2：我们将使用多种方法精细绘制这些位点中最健壮的位点。我们将为每个位点生成一系列嵌套的同源系，并在遗传和手术致敏剂的背景下分析它们的表型效应。同时，我们将继续生成新的自交系的作图数据，利用祖先的单倍型共享模式来描绘位点。我们还将确定在心脏表达中显示菌株特异性差异的基因。目的3：我们将使用小鼠转基因和敲除方法研究Hrtfm2位点的一个令人信服的候选基因。随着其他基因座的其他强候选基因被确定，最引人注目的基因将经历同样的功能丧失和功能获得验证。我们项目的长期目标是在小鼠中确定候选心力衰竭修饰基因，以便在人类心肌病人群中进行评估。这些基因修饰因子的鉴定和表征将增加我们对心肌病和心力衰竭发生和发展的分子机制的理解。

DESCRIPTION (provided by applicant): Heart failure is a significant cause of death worldwide with a number of cardiac etiologies including systolic dysfunction due to cardiomyopathy. However, the prognosis of cardiomyopathy is highly variable among patients, due to undiscovered genetic differences in the population. Identification of genetic risk factors that contribute to these variable outcomes has been refractory to nearly all approaches except for the analysis of candidate genes chosen for obvious biological plausibility. Our project will use an unbiased genetic mapping approach in the mouse to identify novel genes that modulate the progression and outcome of cardiomyopathy. In a well-studied mouse model of dilated cardiomyopathy (the Calsequestrin transgenic mouse), we discovered dramatic strain-specific differences in both disease progression and survival. Using a QTL mapping approach in multiple crosses, we have identified seven distinct genetic loci, Hrtfm1-7 (Heart failure modifier), that alter the disease progression. These loci are currently being isolated in congenic lines. Aim 1: We will phenotypically validate the isolated modifier loci in two distinct cardiomyopathic disease contexts; (1) with the original CSQ transgene as a genetic sensitizer and (2) with a surgical sensitizer using pressure overload induced by aortic constriction. The isolated loci that show robust effects in both models will receive priority for further investigation. Aim 2: We will fine-map the most robust of these loci using multiple approaches. We will generate a series of nested congenic lines for each locus and analyze their phenotypic effects in the context of both the genetic and surgical sensitizers. In parallel, we will continue to generate mapping data with new inbred strains to take advantage of ancestral haplotype sharing patterns to delineate the loci. We will also identify genes that show strain-specific differences in heart expression. Aim 3: We will investigate a compelling candidate gene for the Hrtfm2 locus using mouse transgenic and knockout approaches. As other strong candidate genes are identified for the other loci, the most compelling will undergo this same loss-of-function and gain-of-function validation. Our project's long-term goal is to identify candidate heart-failure modifier genes in the mouse for evaluation in the human cardiomyopathy population. Identification and characterization of these genetic modifiers will increase our understanding of the molecular mechanisms underlying the development and progression of cardiomyopathy and heart failure.