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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

基本信息

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
项目类别：
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

项目摘要

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.