Genetic Determinants of Limb Pathology in Peripheral Artery Disease

周围动脉疾病肢体病理学的遗传决定因素

• 批准号: 8962372
• 负责人: JOSEPH Matthew MCCLUNG
• 金额: $ 37.29万
• 依托单位: EAST CAROLINA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-10 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8962372
• 关键词: Address; Affect; Alleles; Amputation; Arteries; Atherosclerosis; Atrophic; Automobile Driving; Autophagocytosis; Autophagosome; BCL2 gene; Biochemical; Biology; Blood Vessels; Cardiovascular Diseases; Cessation of life; Chronic; Clinical; Code; Coronary Arteriosclerosis; Data; Defect; Dependovirus; Diagnostic; Disease; Endothelial Cells; Endothelium; Excision; Exertion; Gangrene; Genes; Genetic; Genetic Determinism; Genetic Polymorphism; Growth; Heat shock proteins; Human; Hypoxia; Image; In Vitro; Inbred BALB C Mice; Inbred Strains Mice; Individual; Injury; Intermittent Claudication; Intervention; Ischemia; Isolated limb perfusion; Lasers; Limb Salvage; Limb structure; Link; Lower Extremity; Measures; Mediating; Mediator of activation protein; Modeling; Morbidity - disease rate; Mus; Muscle; Muscle Cells; Muscle Fibers; Myopathy; Natural regeneration; Necrosis; Pain; Paracrine Communication; Pathogenesis; Pathology; Patients; Perfusion; Perinatal; Peripheral; Peripheral arterial disease; Phenotype; Play; Predisposition; Proteins; Publishing; Quality Control; Quantitative Trait Loci; Recovery; Resistance; Rest; Risk; Role; Severities; Signal Transduction; Skeletal Muscle; Stem cells; Testing; Therapeutic; Tissue Survival; Tissues; Variant; Work; cellular targeting; clinical phenotype; density; design; effective therapy; gain of function; genetic regulatory protein; improved; in vivo; in vivo Model; insight; loss of function; mortality; neovascularization; novel; pre-clinical; prevent; protective effect; public health relevance; recombinase; response; skeletal; tissue regeneration; tool

 DESCRIPTION (provided by applicant): Peripheral artery disease (PAD) is caused by atherosclerosis of the peripheral arteries, most commonly in the lower extremities, and is nearly as prevalent as coronary artery disease (CAD), with 8-12 million individuals affected in the US. 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). 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. Evidence suggests that genetic differences play a role in the susceptibility to PAD, as inbred mouse strains have dramatically different responses to hind limb ischemia (HLI), a model of PAD. In C57BL/6 (BL6) mice, limb perfusion recovers without tissue loss, whereas BALB/c mice display poor recovery of limb perfusion and significant tissue necrosis, analogous to clinical CLI. In a screen for genes regulating limb survival in the mouse HLI model, a highly significant quantitative trait locus (Lsq 1) was identified. Lsq-1 contains the gene for Bcl-2-associated athanogene-3 (Bag3), which is required for skeletal myofiber survival and regeneration. Preliminary studies demonstrate that a single BAG3 polymorphism results in dramatic phenotypic differences in hypoxic skeletal muscle cells in vitro and in the mouse HLI model in vivo. Expression of the parental BALB/c variant, BAG3Met81, leads to skeletal myofiber atrophy and limb necrosis in vivo. In contrast, the BL6 variant, BAG3Ile81, completely rescues these defects with increases in myofiber size and vascular density in treated muscle. The central hypothesis of this proposal is that BAG3 variants are responsible for muscle survival and tissue loss with ischemia. To test this hypothesis, the Specific Aims of this proposal are to: 1) Determine the effects of BAG3 gain of function on skeletal muscle tissue necrosis and perfusion following limb ischemia in vivo; 2) Determine the cellular origin of BAG3's vascular effects in ischemia; and 3) Determine whether the protective role of BAG3 in ischemia is due to effects on autophagy. Although progress has been made in elucidating the contribution of genetic factors to PAD, identifying factors that modulate patients' susceptibility to CLI will be critical to understanding disease pathogenesis and in developing approaches to promote limb salvage for CLI and other ischemic diseases that currently lack effective treatments.

 描述（由申请人提供）：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，几乎与冠状动脉疾病 (CAD) 一样普遍，有 8-1200 万人受到影响。 PAD 表现为间歇性跛行（IC，劳累时疼痛，休息后可缓解）或严重肢体缺血（CLI，休息时疼痛，伴有或不伴有组织坏死）与 IC 相比，CLI 的发病率和死亡率要高得多；CLI 患者一年内发生严重截肢或死亡的风险接近 40%，有证据表明，与近交系小鼠一样，遗传差异在 PAD 易感性中发挥着重要作用。对后肢缺血（HLI）（一种 PAD 模型）的反应截然不同。在 C57BL/6 (BL6) 小鼠中，肢体灌注恢复而没有组织损失，而 BALB/c 小鼠。显示肢体灌注恢复不良和明显的组织坏死，类似于临床 CLI 中的基因筛查。 在小鼠 HLI 模型中调节肢体存活，这是一个高度显着的数量性状基因座（Lsq Lsq-1 含有 Bcl-2 相关的 athanogene-3 (Bag3) 基因，该基因是骨骼肌纤维存活和再生所必需的。初步研究表明，单一 BAG3 多态性会导致缺氧骨骼的显着表型差异。亲本 BALB/c 变体 BAG3Met81 的表达可在体外和小鼠 HLI 模型中产生。相比之下，BL6 变体 BAG3Ile81 通过增加治疗肌肉中的肌纤维尺寸和血管密度来完全挽救这些缺陷。该提议的中心假设是 BAG3 变体负责肌肉存活和恢复。为了检验这一假设，该提案的具体目标是： 1) 确定 BAG3 功能获得对骨骼肌的影响。体内肢体缺血后的组织坏死和灌注；2) 确定 BAG3 在缺血中的血管作用的细胞起源；以及 3) 确定 BAG3 在缺血中的保护作用是否是由于对自噬的影响。遗传因素对 PAD 的影响，确定调节患者对 CLI 易感性的因素对于了解疾病发病机制和开发促进保肢的方法至关重要针对 CLI 和其他目前缺乏有效治疗方法的缺血性疾病。