Variant Determinants of African American Limb Pathology in Peripheral Arterial Disease

外周动脉疾病中非裔美国人肢体病理学的变异决定因素

• 批准号: 10589077
• 负责人: JOSEPH Matthew MCCLUNG
• 金额: $ 64.5万
• 依托单位: EAST CAROLINA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589077
• 关键词: Adenoviruses; Affect; African American; African American population; African ancestry; Amino Acids; Amputation; Apoptosis; Arteries; Atherosclerosis; Automobile Driving; BCL2 gene; Bioenergetics; Biological; Blood Vessels; Blood flow; Cardiac; Cardiomyopathies; Cardiovascular Diseases; Cardiovascular system; Cell Separation; Cells; Cellular biology; Cessation of life; Clinical; Code; Communication; Data; Dilated Cardiomyopathy; Disease; Disease Outcome; Disparity; Endothelial Cells; Environment; Exertion; Gangrene; Genes; Genetic; Genetic Models; Glycolysis; Hindlimb; Histologic; Human; In Vitro; Inbred BALB C Mice; Incidence; Individual; Injury; Intermittent Claudication; Ischemia; Laboratories; Leg; Limb structure; Link; Lower Extremity; Mediating; Medical; Metabolic; Mitochondria; Modeling; Molecular Chaperones; Morbidity - disease rate; Mus; Muscle; Muscle Cells; Muscle Fibers; Muscle Mitochondria; Mutation; Myocardium; Myopathy; Natural regeneration; Outcome; Outcome Measure; Pain; Pathology; Patient-Focused Outcomes; Patients; Perfusion; Peripheral; Peripheral arterial disease; Pharmaceutical Preparations; Phenotype; Physiological; Pre-Clinical Model; Preclinical Testing; Prevention; Procedures; Process; Proliferating; Proteins; Quantitative Trait Loci; Race; Recovery; Research; Research Personnel; Rest; Risk; Role; Scaffolding Protein; Skeletal Muscle; Striated Muscles; Surgeon; Testing; Therapeutic; Therapeutic Effect; Tissues; Transgenic Organisms; Variant; Vascularization; Virus; Work; angiogenesis; biobank; cell type; cohort; complex IV; critical limb Ischemia; cytochrome c oxidase; demographics; density; design; gene therapy; genetic variant; improved; in vivo; innovation; limb ischemia; mitochondrial dysfunction; mortality; mouse genetics; muscle regeneration; myogenesis; necrotic tissue; neovascularization; novel; overexpression; paracrine; patient population; pleiotropism; preclinical study; public health relevance; racial disparity; restoration; screening; skeletal; targeted treatment; therapeutic candidate; therapeutic development; therapeutically effective; therapy design; tool; translational scientist

Abstract Peripheral artery disease (PAD) is caused by atherosclerosis of the peripheral arteries, most commonly in the lower extremities, and affects 8-12 million individuals in the U.S. Cilastozol was the last drug approved to treat patients with PAD (1999) and twenty years of trials and pre-clinical testing have failed to advance therapeutics. PAD presents as either intermittent claudication (IC; pain with exertion that is relieved with rest) or critical limb ischemia (CLI; pain at rest with or without tissue necrosis or gangrene). Although less common than IC, CLI carries a substantially higher morbidity and mortality; CLI patients have a risk of major amputation or death that approaches 40% in one year. Differences in the clinical course of IC and CLI together with results of recent pre- clinical studies raise the intriguing possibility that IC and CLI represent distinct phenotypic manifestations of the same disease process. We propose an innovative idea; regenerating and functionally competent skeletal muscle supports ischemic neovascularization and vessel maturation - ultimately leading to the recovery of tissue blood flow and the prevention of tissue loss. Our proposal will directly test the ability of ischemic cells in the local limb microenvironment to alter tissue outcomes. We will interrogate the role of human BAG3 (Bcl-2 associated athanogene 3 - an evolutionarily conserved 575 amino acid protein) specifically in the limb muscle and endothelial cells of patients and mice. BAG3 is a multifunctional scaffolding protein and co-chaperone with pleiotropic effects in heart and skeletal muscle. It is a promising genetic candidate for therapeutic development in PAD for the following reasons: 1) mutations in BAG3 cause muscle myofibrillar myopathy and dilated cardiomyopathy in humans, 2) BAG3 variants exist in both African Americans with CLI (a demographic disproportionately affected by PAD - Preliminary Data) and cardiomyopathy, and 3) a murine coding variant in BAG3 regulates muscle regeneration, vascular density, and limb survival in a pre-clinical model of PAD (hindlimb ischemia-HLI). To that end, this proposal brings together clinical vascular surgeons, a skeletal muscle biologist who focuses on physiologic outcome measures, a biochemist and mitochondrial biologist who focuses on interrogating mitochondrial form and function in disease, a clinical cardiologist and researcher, and a translational scientist who studies skeletal muscle adaptability to injury and endothelial cell biology and has developed an unparalleled biobank of human PAD tissues. The central hypothesis of this proposal states that genetic variants in BAG3 result in myopathy and mitochondriopathy that disrupts communication between muscle and endothelial cells and results in a local muscle environment insufficient to support the vasculature. To that end, the Specific Aims are: 1) In PAD relevant models, determine the functional link between ischemic myopathy and angiogenesis. 2) Determine whether Cox6a2 expression is sufficient to rescue BAG3 variant induced myopathy in PAD conditions. 3) Establish whether BAG3 variants are a link between AA race and differences in CLI patient outcomes.

抽象的 外围动脉疾病（PAD）是由周围动脉的动脉粥样硬化引起的，最常见于 下肢，影响美国8-1200万个人西拉斯特二酚是批准治疗的最后一种药物 PAD患者（1999）和二十年的试验和临床前测试未能提高治疗疗法。 垫出现是间歇性lau不平的（ic;休息后能缓解劳累的疼痛）或关键的肢体 缺血（CLI；有或没有组织坏死或坏疽的休息时疼痛）。虽然不如IC常见，但CLI 发病率和死亡率要高得多； CLI患者有重大截肢或死亡的风险 一年内接近40％。 IC和CLI临床过程的差异以及最近的前 临床研究提出了一个有趣的可能性，即IC和CLI代表了不同的表型表现。 相同的疾病过程。我们提出了一个创新的想法。再生和功能能力的骨骼肌 支持缺血性新血管形成和血管成熟 - 最终导致组织血液恢复 流量和预防组织损失。我们的建议将直接测试局部肢体缺血细胞的能力 微环境改变组织结局。我们将询问人类Bag3的作用（Bcl-2相关 Athanogene 3-一种进化保守的575氨基酸蛋白），特别是在肢体肌肉中 患者和小鼠的内皮细胞。 Bag3是一种多功能脚手架蛋白质，并与 心脏和骨骼肌的多效性作用。这是治疗发育的有前途的遗传候选者 出于以下原因的垫子中：1）BAG3中的突变引起肌肉肌原纤维肌病并扩张 人类的心肌病，2）两位非洲裔美国人都有CLI的Bag3变种（人群 受PAD的影响不成比例 - 初步数据）和心肌病，以及3）鼠编码变体 BAG3调节在pAD前临床模型中调节肌肉再生，血管密度和肢体存活（后肢 缺血-HLI）。为此，该提案汇集了骨骼肌肉生物学家临床血管外科医生 专注于生理结果指标的人，一位专注于生物化学家和线粒体生物学家 询问线粒体形式和疾病的功能，临床心脏病专家和研究人员，转化 研究骨骼肌对损伤和内皮细胞生物学的适应性的科学家，并发展了 人垫组织的无与伦比的生物库。该提议的中心假设指出遗传 BAG3中的变体导致肌病和线粒体病，破坏了之间的沟通 肌肉和内皮细胞，导致局部肌肉环境不足以支持 脉管系统。为此，具体目的是：1）在板相关模型中，确定功能链接 在缺血性肌病和血管生成之间。 2）确定COX6A2表达是否足以营救 BAG3变体在垫条件下诱导肌病。 3）确定BAG3变体是否是AA之间的链接 CLI患者预后的种族和差异。

项目成果

Muscle progenitor cells are required for skeletal muscle regeneration and prevention of adipogenesis after limb ischemia.

• DOI: 10.3389/fcvm.2023.1118738
• 发表时间: 2023
• 期刊: FRONTIERS IN CARDIOVASCULAR MEDICINE
• 影响因子: 3.6
• 作者: Abbas, Hasan;Olivere, Lindsey A.;Padgett, Michael E.;Schmidt, Cameron A.;Gilmore, Brian F.;McCord, Timothy J.;Southerland, Kevin W.;McClung, Joseph M.;Kontos, Christopher D.
• 通讯作者: Kontos, Christopher D.

Isometric skeletal muscle contractile properties in common strains of male laboratory mice.

• DOI: 10.3389/fphys.2022.937132
• 发表时间: 2022
• 期刊: Frontiers in physiology
• 影响因子: 4