Gene-by-sex interactions in heart failure with preserved ejection fraction (HFpEF)

项目2：保留射血分数(HFpEF)的心力衰竭患者的基因与性别的相互作用 项目总结 在过去的两年中，我们的实验室一直对心脏代谢特征的性别差异基础感兴趣 几十年。我们使用了一种“系统遗传学”方法，将临床和分子特征结合在一起 遗传变异。对于小鼠的研究，我们使用一种名为杂交小鼠多样性小组(HMDP)的资源，该小组 在研究复杂性状方面有许多优势。我们的建议是建立在一个知之甚少的问题上，但是 常见的心力衰竭称为保留射血分数的心力衰竭(HFpEF)。它的特点是 由于舒张期功能障碍和保留的射血分数，与射血分数降低的心力衰竭不同 (HFrEF)。HFpEF是一种高度复杂的疾病，有多种并存，包括肥胖、糖尿病、 高血压和炎症。它是高度异质性的，并且具有重要的环境成分， 使人类研究变得困难。一致的流行病学数据表明，女性的发病率大约是 与男性相比，更有可能发展为HFpEF。他们还倾向于表现出更多的症状负担，包括 fi可显著增加舒张期功能不全，增加左心室僵硬。然而，性的本质 分歧仍不明朗。由于该综合征的复杂性，我们使用了一种小鼠模型 HFpEF包括喂给小鼠高脂饮食和一氧化氮合酶抑制剂。我们的战略是执行 在HMDP中使用该模型进行系统遗传学分析，并由此提出可测试的假设 在人类群体中。到目前为止，我们在老鼠身上的结果表明，雌性往往更容易受到舒张压的影响。 与男性相比，HFpEF功能障碍和其他特征，符合人类流行病学数据。目标1是 旨在了解HFpEF特征的性别差异，特别是在分子水平上的心脏。一个很长的- 学期目标是建立可推广到人类的特定性别生物网络的模型。目标2针对的是 了解性别差异的原因。我们之前获得的证据表明性激素 部分地解释了HFpEF易感性的性别差异，我们现在建议检查性染色体 使用四种核心基因型别(FCG)。在研究过程中，我们发现，在内心深处，男性 拥有比女性更高水平的线粒体功能，我们提出这可能解释了 性别差异。在目标3中，我们现在将通过检查雌激素受体α和雌激素受体的作用来检验这一假说。 线粒体功能中的性染色体。我们还将详细描述线粒体酶， ACSL6，我们已确定为HFpEF的原因。

Project 2: Gene-by-sex interactions in heart failure with preserved ejection fraction (HFpEF) PROJECT SUMMARY Our laboratory has been interested in the basis of sex differences in cardiometabolic traits for the past two decades. We use a “system genetics” approach that integrates clinical and molecular traits in the context of genetic variation. For studies in mice we use a resource called the Hybrid Mouse Diversity Panel (HMDP) that has a number of advantages for studies of complex traits. Our proposal is fucused on a poorly understood, but common form of heart failure, called heart failure with preserved ejection fraction (HFpEF). It is characterized by diastolic dysfunction and preserved ejection fraction, distinct from heart failure with reduced ejection fraction (HFrEF). HFpEF is a highly complex disorder with multiple comorbidities, including obesity, diabetes, hypertension, and inflammation. It is highly heterogenous and has a significant environmental component, making human studies difficult. Consistent epidemiological data demonstrate that women are about twice as likely to develop HFpEF as compared to men. They also tend to present with more symptom burden, including significantly increased diastolic dysfunction and enhanced left ventricle stiffness. However, the nature of sex differences remains unclear. Because of the complexity of the syndrome, we have used a mouse model of HFpEF that involves feeding mice a high fat diet and a nitric oxide synthase inhibitor. Our strategy is to perform systems genetics analyses using this model in the HMDP and from this develop hypotheses that can be tested in human cohorts. Our results thus far in mice have revealed that females tend to be more susceptible to diastolic dysfunction and other HFpEF traits than males, consistent with the human epidemiological data. Aim 1 is directed at understanding sex differences in HFpEF traits, particularly in the heart, at the molecular level. A long- term goal is to model sex-specific biologic networks that can be generalized to humans. Aim 2 is directed at understanding the cause of the sex differences. We have previously obtained evidence that sex hormones explain, in part, the sex differences in HFpEF susceptibility and we now propose to examine sex chromosomes using the Four Core Genotypes (FCG). During the course of our studies, we discovered that, in heart, males have higher levels of mitochondrial function than do females, and we have proposed that this may explain the sex difference. In Aim 3, we will now test this hypothesis by examining the roles of estrogen receptor alpha and sex chromosomes in mitochondrial functions. We will also characterize in detail the mitochondrial enzyme, ACSL6, that we have identified as causal for HFpEF.