Cell type-specific function of the mineralocorticoid receptor in pulmonary hypertension and associated right heart failure

盐皮质激素受体在肺动脉高压和相关右心衰竭中的细胞类型特异性功能

• 批准号: 428371883
• 负责人: Privatdozent Dr. Achim Lother
• 金额: --
• 依托单位: Abteilung II
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/428371883?language=en
• 关键词: Cell; type; specific; function; mineralocorticoid

Pulmonary hypertension (PH) and subsequent right ventricular remodeling are associated with high morbidity and poor outcome. Aldosterone and its receptor, the mineralocorticoid receptor (MR), are key mediators of cardiovascular disease. Preclinical and early clinical data show beneficial effects of MR antagonists on pulmonary artery pressure and right ventricular function. However, their clinical use is limited by adverse effects on renal function. A precise understanding of the cellular and molecular function of MR in PH and right ventricular remodeling might foster new therapeutic innovation to separate beneficial from adverse effects.The pathophysiology of PH and right ventricular failure involves various cell types in the pulmonary vasculature and the heart that express MR. As a ligand-activated transcription factor, MR mediates many of its effects via regulation of gene expression. Chromatin accessibility and transcriptional activity of MR are modulated by epigenetic modifications and interaction with other transcription factors. The aims of this project are 1) to identify the cell types in which MR is relevant for PH and right ventricular remodeling using cell type-specific MR deletion mouse models, 2) to determine molecular mechanisms that modulate transcriptional control by MR by deciphering the specific transcriptome and epigenome of these cells, and 3) to evaluate the impact of pharmacological MR inhibition on transcriptomic and epigenetic changes in PH and right ventricular remodeling.The mechanistic insights gained in this project will set the basis for future studies that aim to identify new pharmacological targets and might lead to the development of cell type-specific inhibitors of the MR signaling pathway for the treatment of PH and right ventricular remodeling.

肺动脉高压（PH）和随后的右心室重构与高发病率和不良结局相关。醛固酮及其受体，盐皮质激素受体（MR），是心血管疾病的关键介质。临床前和早期临床数据显示MR拮抗剂对肺动脉压和右心室功能的有益作用。然而，它们的临床使用受到对肾功能的不良影响的限制。准确理解MR在PH和右心室重构中的细胞和分子功能可能会促进新的治疗创新，以区分有益和不良反应。PH和右心室衰竭的病理生理学涉及肺血管和心脏中表达MR的各种细胞类型。作为配体激活的转录因子，MR通过调节基因表达介导其许多作用。染色质可及性和MR的转录活性受表观遗传修饰和与其他转录因子的相互作用调节。该项目的目的是1）使用细胞类型特异性MR缺失小鼠模型鉴定MR与PH和右心室重塑相关的细胞类型，2）通过破译这些细胞的特异性转录组和表观基因组来确定调节MR转录控制的分子机制，和3）评估药物MR抑制对PH和右心室重构的转录组学和表观遗传学变化的影响。本项目中获得的机制见解将为未来的研究奠定基础。旨在确定新药理学靶点的研究，可能导致开发MR信号通路的细胞类型特异性抑制剂，用于治疗PH和右心室重塑。