Identification of genetics modifiers of heart diease

描述（由申请方提供）：心力衰竭是全球范围内的一种重要死亡原因，有多种心脏病因，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中存在很大差异。除了分析选择的具有明显生物相容性的候选基因外，几乎所有方法都难以识别导致这些可变结果的遗传风险因素。我们的项目将在小鼠中使用无偏倚的遗传作图方法来鉴定调节心肌病进展和结果的新基因。在一个经过充分研究的扩张型心肌病小鼠模型（钙螯合蛋白转基因小鼠）中，我们发现了疾病进展和存活率的显着菌株特异性差异。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，Hrtfm 1 -7（心力衰竭修饰因子），改变疾病的进展。这些基因座目前正在同类系中分离。目标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CSQ转基因作为遗传致敏剂和（2）使用由主动脉缩窄诱导的压力超负荷的手术致敏剂。在两个模型中显示稳健效应的孤立位点将优先进行进一步研究。目标2：我们将使用多种方法精细映射这些位点中最稳健的。我们将为每个位点产生一系列嵌套同源系，并在遗传和手术致敏剂的背景下分析其表型效应。与此同时，我们将继续利用新的近交系产生作图数据，以利用祖先单倍型共享模式来描绘基因座。我们还将鉴定在心脏表达中显示菌株特异性差异的基因。目的3：我们将研究一个引人注目的候选基因的Hrtfm 2位点使用小鼠转基因和敲除的方法。随着其他强候选基因被鉴定为其他基因座，最引人注目的将经历这种相同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鉴定候选的心力衰竭修饰基因，以用于在人类心肌病人群中进行评估。这些遗传修饰剂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.