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

基本信息

批准号：
10187852
负责人：
JOSEPH Matthew MCCLUNG
金额：
$ 67.37万
依托单位：
EAST CAROLINA UNIVERSITY
依托单位国家：
美国
项目类别：
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/10187852
关键词：
Adenoviruses Affect African African American 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

项目摘要

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.

抽象的外周动脉疾病（PAD）是由外周动脉粥样硬化引起的，最常见于下肢，影响美国 8-1200 万人。西拉斯托唑是最后一种被批准用于治疗的药物 PAD 患者（1999）和二十年的试验和临床前测试未能推进治疗。 PAD 表现为间歇性跛行（IC；用力时疼痛，休息后可缓解）或严重肢体缺血（CLI；静息时疼痛，伴或不伴组织坏死或坏疽）。尽管不如 IC 常见，但 CLI 发病率和死亡率显着升高； CLI 患者有严重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预检结果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发病过程。我们提出一个创新的想法；骨骼肌的再生和功能能力支持缺血性新生血管形成和血管成熟——最终导致组织血液的恢复流动和防止组织损失。我们的方案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。我们将探讨人类 BAG3（Bcl-2 相关 athanogene 3 - 一种进化上保守的 575 个氨基酸蛋白质），特别是在肢体肌肉和患者和小鼠的内皮细胞。 BAG3 是一种多功能支架蛋白和共伴侣蛋白对心脏和骨骼肌的多效性作用。它是一种有前途的治疗开发候选基因在PAD中，原因如下：1）BAG3突变导致肌肉肌原纤维肌病和扩张人类心肌病，2) BAG3 变体存在于患有 CLI 的非裔美国人（人口统计不成比例地受到 PAD（初步数据）和心肌病的影响，以及 3）小鼠编码变异 BAG3 在 PAD 临床前模型（后肢）中调节肌肉再生、血管密度和肢体存活缺血-HLI）。为此，该提案汇集了临床血管外科医生、骨骼肌生物学家专注于生理结果测量的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，临床心脏病学家和研究人员，以及转化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类 PAD 组织生物库。该提案的中心假设指出，遗传 BAG3 的变异会导致肌病和线粒体病，从而扰乱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，具体目标是： 1）在PAD相关模型中，确定功能链接缺血性肌病和血管生成之间。 2) 确定Cox6a2表达是否足以挽救 BAG3 变异在 PAD 条件下诱发肌病。 3) 确定BAG3变体是否是AA之间的联系 CLI 患者结果的种族和差异。