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: 10375535
• 负责人: JOSEPH Matthew MCCLUNG
• 金额: $ 64.87万
• 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/10375535
• 关键词: Adenoviruses; Affect; African American; African American population; African ancestry; Amino Acids; Amputation; Apoptosis; Arteries; Atherosclerosis; Automobile Driving; BAG3 gene; BCL2 gene; Bioenergetics; Biological; Blood Vessels; Blood flow; Cardiac; Cardiomyopathies; Cardiovascular Diseases; Cardiovascular system; Cells; Cellular biology; Cessation of life; Clinical; Code; Communication; Data; Dilated Cardiomyopathy; Disease; Disease Outcome; 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; Proteins; Quantitative Trait Loci; Recovery; Research; Research Personnel; Rest; Risk; Role; Scaffolding Protein; Skeletal Muscle; Striated Muscles; Surgeon; Testing; Therapeutic; Therapeutic Effect; Tissues; Transgenic Organisms; Variant; Virus; Work; angiogenesis; attenuation; base; 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 difference; 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.

摘要 外周动脉疾病(PAD)是由外周动脉粥样硬化引起的，最常见的是 西拉托唑是最后一种被批准用于治疗的药物。 PAD患者(1999)和20年来的试验和临床前测试都未能推进治疗。 PAD表现为间歇性跛行(IC；劳累疼痛，休息后缓解)或危重肢体 缺血(CLI；静息时疼痛，或不伴有组织坏死或坏疽)。虽然不如IC、CLI常见 具有显著更高的发病率和死亡率；CLI患者有重大截肢或死亡的风险， 一年内接近40%。IC和CLI的临床病程差异及近期治疗前的结果 临床研究提出了一种有趣的可能性，即IC和CLI代表着不同的表型表现 同样的疾病过程。我们提出了一个创新的想法：再生和具有功能能力的骨骼肌 支持缺血新生血管和血管成熟-最终导致组织血液的恢复 流畅，防止组织流失。我们的建议将直接测试局部肢体缺血细胞的能力 改变组织结果的微环境。我们将询问人类BAG3(相关的Bcl2)的作用 一种进化上保守的575个氨基酸的蛋白质)，专存在于肢体肌肉和 病人和小鼠的内皮细胞。BAG3是一种多功能支架蛋白和辅助伴侣蛋白，与 心脏和骨骼肌的多效性效应。它是一种很有希望用于治疗开发的候选基因。 导致PAD的原因如下：1)BAG3基因突变导致肌原纤维肌病和扩张 人类的心肌病，2)BAG3变异存在于患有CLI的两个非裔美国人中(人口统计学 不成比例地受PAD-初步数据的影响)和心肌病，以及3)小鼠编码变体 BAG3在PAD(后肢)临床前模型中调节肌肉再生、血管密度和肢体存活 缺血-HLI)。为此，这项提议汇集了临床血管外科医生、骨骼肌生物学家 世卫组织专注于生理结果测量，一位生物化学家和线粒体生物学家，专注于 询问疾病中线粒体的形式和功能，临床心脏病专家和研究人员，以及翻译 研究骨骼肌对损伤的适应性和内皮细胞生物学的科学家，并开发了一种 无与伦比的人体垫组织生物库。这一提议的中心假设是，基因 BAG3基因的变异会导致肌病和线粒体病，从而扰乱 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，具体目标是：1)在PAD的相关模型中，确定功能环节 缺血性肌病和血管生成之间的关系。2)确定Cox6a2的表达是否足以挽救 在PAD状态下，BAG3变异体诱导的肌病。3)确定BAG3变异是否是AA之间的链接 种族和CLI患者预后的差异。