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: 9264027
• 负责人: JOSEPH Matthew MCCLUNG
• 金额: $ 38.26万
• 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/9264027
• 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; Enterobacteria phage P1 Cre recombinase; Excision; Exertion; Gangrene; Genes; Genetic; Genetic Determinism; Genetic Polymorphism; Growth; Heat shock proteins; Human; Hypoxia; 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; perfusion imaging; pre-clinical; prevent; protective effect; public health relevance; 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（由适用提供）：周围动脉疾病（PAD）是由外围动脉的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，在美国有8-1200万个人。 PAD表现为间歇性的laurauration（IC，休息或关键的肢体缺血而缓解劳累的疼痛（CLI，疼痛，有或没有IC不常见的情况下，CLI的发病率和死亡率更高； CLI患者具有重大截肢或死亡的风险，有证据表明有40％的差异表明，远处的角色是构成鼠标的角色。对后肢缺血（HLI）的反应，C57BL/6（BL6）小鼠的模型，肢体灌注恢复而无需组织损失，而BALB/C小鼠的肢体灌注恢复不佳，与临床中的筛查相似。 调节小鼠HLI模型中的肢体存活，这是一个高度显着的定量特质基因座（LSQ 1）确定。 LSQ-1包含与Bcl-2相关的Athanogene-3（BAG3）的基因，这是骨骼肌纤维生存和再生所必需的。初步研究表明，单个BAG3多态性导致体外和小鼠HLI模型在体外的低氧骨骼肌细胞中产生巨大的表型差异。父母BALB/C变体的表达Bag3met81导致体内骨骼肌纤维萎缩和肢体坏死。相比之下，BL6变体Bag3ile81完全反应这些缺陷，而处理的肌肉中的肌纤维大小和血管密度的增加。该提议的中心假设是BAG3变体负责缺血的肌肉存活和组织丧失。为了检验该假设，该提案的具体目的是：1）确定BAG3功能对体内肢体缺血后骨骼肌组织坏死和灌注的影响； 2）确定Bag3缺血中BAG3血管作用的细胞起源； 3）确定BAG3在缺血中的受保护作用是否是由于对自噬的影响。尽管在阐明遗传因素对PAD的贡献方面取得了进展，但识别调节患者对CLI易感性的因素对于理解疾病发病机理以及开发方法来促进CLI和其他目前缺乏有效治疗的缺血性疾病的方法至关重要。