Cell State Specific modifiers of pathological cardiac remodeling

项目摘要： 在患有遗传性和获得性心肌病的个体中存在相当大的疾病变异， 表明修饰剂显著改变这些疾病的进展。即使在相关的个体中 携带相同的基因突变，病理性心脏重塑可能完全不同。的识别 心肌病修饰物对于理解心肌细胞如何适应病理刺激非常重要 并最终可能导致新的治疗靶点。成年哺乳动物心肌细胞对许多 不同的病理应激源通过发展细胞肥大。心肌细胞肥大继发于 基因突变越来越被认为是心力衰竭和猝死的常见原因， 青少年和成年人。我们利用多种动物模型发现糖皮质激素受体（GR） 信号传导改变心肌细胞肥大信号传导途径。重要的是，分析心脏组织， 患有肥厚型心肌病的人证实，糖皮质激素受体信号转导失调， 在人类疾病的发病机制中很重要。基于这些发现，我们假设细胞状态 特异性糖皮质激素信号转导修饰心肌细胞应激反应途径。调查这一 假设我们将执行以下具体目标：目标1：定义GR反式激活的贡献， 反式阻遏在调节病理性心肌细胞反应中的作用。目标2：确定GR的作用 伴侣蛋白FKBP 5在调节心肌细胞应激反应中的作用。目的3：定义心肌细胞GR 基础状态和疾病状态下的转录辅助调节因子。一旦完成，这些创新的研究将提供 GR信号如何改变心肌细胞对病理刺激的适应， 遗传性和获得性心肌病的新治疗靶点。这是非常重要的，因为 目前，对这些疾病的治疗选择有限。

Project Summary: Considerable disease variation exists across individuals with both inherited and acquired cardiomyopathies, suggesting that modifiers significantly alter the progression of these diseases. Even in related individuals carrying identical genetic mutations, pathological cardiac remodeling can be quite different. The identification of cardiomyopathy modifiers is highly important to understand how cardiomyocytes adapt to pathological stimuli and, ultimately, may lead to novel therapeutic targets. Adult mammalian cardiomyocytes respond to many different pathological stressors by developing cellular hypertrophy. Cardiomyocyte hypertrophy secondary to genetic mutations is increasingly recognized as a common cause of heart failure and sudden death in both adolescents and adults. We utilized multiple animal models to discover that glucocorticoid receptor (GR) signaling modifies cardiomyocyte hypertrophic signaling pathways. Importantly, analysis of heart tissue from humans with hypertrophic cardiomyopathy confirmed that dysregulated glucocorticoid receptor signaling is important in the pathogenesis of human disease. Based on these findings, we hypothesize that cell state specific glucocorticoid signaling modifies cardiomyocyte stress response pathways. To investigate this hypothesis we will perform the following specific aims: Aim 1: Define the contribution of GR transactivation and transrepression in regulating pathological cardiomyocyte responses. Aim 2: Determine the role of the GR chaperone FKBP5 in regulating the cardiomyocyte stress response. Aim 3: Define cardiomyocyte GR transcriptional co-regulators in basal and disease states. Once completed, these innovative studies will provide novel insights into how GR signaling modifies cardiomyocyte adaptation to pathological stimuli and will yield new treatment targets for both genetic and acquired cardiomyopathies. This is highly significant because currently there are limited treatment options available for these diseases.