Functions of skeletal muscle mineralocorticoid receptor signaling in chronic and acute injury

骨骼肌盐皮质激素受体信号在慢性和急性损伤中的功能

基本信息

批准号：
10365984
负责人：
Jill A Rafael-Fortney
金额：
$ 36.71万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10365984
关键词：
Acute Age Agonist Aldosterone Angiotensin-Converting Enzyme Inhibitors CYP11B2 gene Cardiac Cardiomyopathies Cardiovascular Diseases Cell Nucleus Cell physiology Cells Chronic Controlled Clinical Trials Data Degenerative Disorder Disease Double-Blind Method Drug Targeting Duchenne cardiomyopathy Duchenne muscular dystrophy Dystrophin Enzymes FDA approved Fiber Gene Expression Gene Expression Regulation Gene Targeting Genetic Transcription Health Heart failure Hormones Human Immune In Vitro Inflammatory Injury Longevity Mineralocorticoid Receptor Mineralocorticoids Modeling Molecular Mus Muscle Muscle Fibers Muscle function Muscular Dystrophies Myocardium Myopathy Natural regeneration Outcome Pathogenesis Pathogenicity Pathologic Pathology Patients Pharmaceutical Preparations Pharmacology Placebo Control Process Production Publishing Receptor Signaling Recording of previous events Role Safety Skeletal Muscle Skeletal muscle injury Striated Muscles Teenagers Testing Therapeutic Time Translating Wheelchairs antagonist base cell injury cell type conditional knockout defined contribution drug efficacy genetic approach in vivo injury and repair mouse model novel preclinical efficacy prevent receptor receptor function regenerative repaired skeletal muscle wasting steroid hormone receptor therapeutic target

项目摘要

PROJECT SUMMARY Mineralocorticoid receptor antagonists are FDA-approved drugs that have a long history of safety and efficacy for treating heart failure. These drugs block activation of mineralocorticoid receptors (MR) by the endogenous mineralocorticoid aldosterone and prevent these steroid hormone receptors from translocating to the nucleus and regulating gene transcription. Chronic overactivation of MR by the natural hormone aldosterone is known to exacerbate cell damage in cardiovascular diseases. We have repeatedly demonstrated that treatment with a MR antagonist plus an angiotensin converting enzyme inhibitor, which acts upstream to inhibit aldosterone production, have therapeutic benefits on both heart and skeletal muscles in mouse models of Duchenne muscular dystrophy. The observed preclinical efficacy of MR antagonists on dystrophic skeletal muscle function and pathology was a surprise, given that MR had never been identified in skeletal muscles. We have now demonstrated that MR are present in skeletal muscles and function in gene expression. We have also shown that MR antagonists prevent ongoing dystrophic muscle damage, supporting these drugs act at an early stage of the pathogenic process. Inflammatory cells present in damaged muscles contain high levels of the enzyme required for aldosterone synthesis and increased levels of aldosterone may contribute to chronic muscle damage in muscular dystrophy. Efficacy of drugs that prevent activation of MR in muscular dystrophy models and the presence of local aldosterone production during chronic and acute skeletal muscle injuries support the scientific premise that MR may be a therapeutic target for chronic skeletal muscle diseases and acute injuries. However, the role of mineralocorticoid receptors in normal skeletal muscle function and pathogenesis is not known. In this application, we will use a genetic approach to dissect MR functions and downstream molecular mechanisms in acute and chronic muscle injuries. Information about the role of these receptors in skeletal muscle will provide the basis for modulating MR as a therapeutic target for a wide variety of muscle pathologies.

项目摘要矿物皮质激素受体拮抗剂是经FDA批准的药物，具有较长的安全史和治疗心力衰竭的功效。这些药物通过内源性盐皮质激素醛固酮，并防止这些类固醇激素受体从转移到细胞核和调节基因转录。 MR的长期过度激活众所周知，天然激素醛固酮会加剧心血管疾病中的细胞损伤。我们有反复证明了MR拮抗剂和血管紧张素转化酶的治疗抑制剂在抑制醛固酮产生的抑制剂方面具有治疗益处 Duchenne肌肉营养不良的小鼠模型中的骨骼肌。观察到的临床前 MR拮抗剂对营养不良的骨骼肌功能和病理的功效令人惊讶，鉴于那MR从未在骨骼肌中被鉴定出来。我们现在已经证明了MR是存在于骨骼肌中，并在基因表达中功能。我们还表明MR拮抗剂防止持续的营养不良肌肉损害，支持这些药物的作用致病过程。受损肌肉中存在的炎性细胞含有高水平的酶醛固酮合成和醛固酮水平升高可能有助于慢性肌肉营养不良的肌肉损伤。阻止MR激活肌肉激活的药物的功效慢性和急性骨骼期间的营养不良模型和局部醛固酮产生的存在肌肉损伤支持科学前提，即MR可能是慢性骨骼的治疗目标肌肉疾病和急性伤害。但是，矿物皮质受体在正常骨骼中的作用肌肉功能和发病机理尚不清楚。在此应用中，我们将使用一种遗传方法在急性和慢性肌肉损伤中剖析MR功能和下游分子机制。有关这些受体在骨骼肌中作用的信息将为调节MR的基础提供基础作为多种肌肉病理的治疗靶标。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mineralocorticoid Receptor Antagonists in Muscular Dystrophy Mice During Aging and Exercise.

DOI：
10.3233/jnd-180323
发表时间：
2018-01-01
期刊：
Journal of neuromuscular diseases
影响因子：
3.3
作者：
Lowe, Jeovanna;Kadakia, Feni K;Janssen, Paul M L
通讯作者：
Janssen, Paul M L

Mineralocorticoid Receptor Signaling in the Inflammatory Skeletal Muscle Microenvironments of Muscular Dystrophy and Acute Injury.

DOI：
10.3389/fphar.2022.942660
发表时间：
2022
期刊：
FRONTIERS IN PHARMACOLOGY
影响因子：
5.6
作者：
Howard, Zachary M.;Gomatam, Chetan K.;Piepho, Arden B.;Rafael-Fortney, Jill A.
通讯作者：
Rafael-Fortney, Jill A.