Cell State Specific modifiers of pathological cardiac remodeling

病理性心脏重塑的细胞状态特异性调节剂

• 批准号: 10186790
• 负责人: Jason Becker
• 金额: $ 39.14万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10186790
• 关键词: Adolescent; Adult; Affect; Agonist; Animal Model; Biological Assay; Biological Models; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cause of Death; Cell Size; Cells; ChIP-seq; Chemicals; DNA Sequence Alteration; Data; Disease; Disease Progression; FAIRE sequencing; Firefly Luciferases; Gene Expression; Gene Mutation; Genes; Genetic; Genetic Transcription; Glucocorticoid Receptor; Glucocorticoids; Heart; Heart failure; Heterogeneity; Human; Hypertrophic Cardiomyopathy; Hypertrophy; Immunoprecipitation; In Vitro; Individual; Inherited; Lead; Ligation; Luciferases; Mass Spectrum Analysis; Mendelian disorder; Methods; Modeling; Molecular Chaperones; Mus; Myocardial; Myocardial tissue; Nuclear; Pathogenesis; Pathologic; Pathway Analysis; Pathway interactions; Patients; Phenotype; Protein Array; Proteins; Receptor Signaling; Regulation; Reporter; Research; Research Proposals; Role; Sarcomeres; Secondary to; Signal Pathway; Signal Transduction; Stimulus; Sudden Death; Tissues; Transactivation; Transgenic Organisms; United States; Variant; Ventricular Remodeling; Zebrafish; base; biological adaptation to stress; chemical genetics; chromatin remodeling; defined contribution; experimental study; genetic approach; human disease; human tissue; in vivo; induced pluripotent stem cell; inherited cardiomyopathy; innovation; insight; new therapeutic target; non-genetic; novel; novel therapeutic intervention; promoter; receptor; response; stressor

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.

项目总结： 遗传性和获得性心肌病的个体之间存在着相当大的疾病差异， 这表明修饰物显著改变了这些疾病的进展。即使是在相关的个人中 携带相同的基因突变，病理性心脏重塑可能会有很大不同。身份的鉴定 心肌病修饰物对于了解心肌细胞如何适应病理性刺激非常重要 最终，可能会产生新的治疗靶点。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。继发性心肌细胞肥大 基因突变越来越被认为是导致心力衰竭和猝死的共同原因。 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) 信号转导可以改变心肌细胞肥大的信号通路。重要的是，分析来自 肥厚型心肌病患者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 特定的糖皮质激素信号改变心肌细胞应激反应通路。来调查这件事 假设我们将执行以下具体目标：目标1：定义GR反式激活和 反式抑制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FKBP5在调节心肌细胞应激反应中的作用目标3：定义心肌细胞GR 基础状态和疾病状态下的转录协同调节。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并将产生 遗传性和获得性心肌病的新治疗目标。这一点意义重大，因为 目前，可用于这些疾病的治疗选择有限。

项目成果

Sarcomere mutation negative hypertrophic cardiomyopathy is associated with ageing and obesity.

• DOI: 10.1136/openhrt-2020-001560
• 发表时间: 2021-03
• 期刊: Open heart
• 影响因子: 2.7
• 作者: de Feria AE;Kott AE;Becker JR
• 通讯作者: Becker JR

Replication Stress Response Modifies Sarcomeric Cardiomyopathy Remodeling.

• DOI: 10.1161/jaha.121.021768
• 发表时间: 2021-08-03
• 期刊: Journal of the American Heart Association
• 影响因子: 5.4
• 作者: Pal S;Nixon BR;Glennon MS;Shridhar P;Satterfield SL;Su YR;Becker JR
• 通讯作者: Becker JR

MDM2 Regulation of HIF Signaling Causes Microvascular Dysfunction in Hypertrophic Cardiomyopathy.

• DOI: 10.1161/circulationaha.123.064332
• 发表时间: 2023-12-05
• 期刊: CIRCULATION
• 影响因子: 37.8
• 作者: Shridhar, Puneeth;Glennon, Michael S.;Pal, Soumojit;Waldron, Christina J.;Chetkof, Ethan J.;Basak, Payel;Clavere, Nicolas G.;Banerjee, Dipanjan;Gingras, Sebastien;Becker, Jason R.
• 通讯作者: Becker, Jason R.