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:10375535
- 负责人:
- 金额:$ 64.87万
- 依托单位:
- 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:
- 关键词:AdenovirusesAffectAfrican AmericanAfrican American populationAfrican ancestryAmino AcidsAmputationApoptosisArteriesAtherosclerosisAutomobile DrivingBAG3 geneBCL2 geneBioenergeticsBiologicalBlood VesselsBlood flowCardiacCardiomyopathiesCardiovascular DiseasesCardiovascular systemCellsCellular biologyCessation of lifeClinicalCodeCommunicationDataDilated CardiomyopathyDiseaseDisease OutcomeEndothelial CellsEnvironmentExertionGangreneGenesGeneticGenetic ModelsGlycolysisHindlimbHistologicHumanIn VitroInbred BALB C MiceIncidenceIndividualInjuryIntermittent ClaudicationIschemiaLaboratoriesLegLimb structureLinkLower ExtremityMediatingMedicalMetabolicMitochondriaModelingMolecular ChaperonesMorbidity - disease rateMusMuscleMuscle CellsMuscle FibersMuscle MitochondriaMutationMyocardiumMyopathyNatural regenerationOutcomeOutcome MeasurePainPathologyPatient-Focused OutcomesPatientsPerfusionPeripheralPeripheral arterial diseasePharmaceutical PreparationsPhenotypePhysiologicalPre-Clinical ModelPreclinical TestingPreventionProceduresProcessProteinsQuantitative Trait LociRecoveryResearchResearch PersonnelRestRiskRoleScaffolding ProteinSkeletal MuscleStriated MusclesSurgeonTestingTherapeuticTherapeutic EffectTissuesTransgenic OrganismsVariantVirusWorkangiogenesisattenuationbasebiobankcell typecohortcomplex IVcritical limb Ischemiacytochrome c oxidasedemographicsdensitydesigngene therapygenetic variantimprovedin vivoinnovationlimb ischemiamitochondrial dysfunctionmortalitymouse geneticsmuscle regenerationmyogenesisnecrotic tissueneovascularizationnoveloverexpressionparacrinepatient populationpleiotropismpreclinical studypublic health relevanceracial differenceracial disparityrestorationscreeningskeletaltargeted treatmenttherapeutic candidatetherapeutic developmenttherapeutically effectivetherapy designtooltranslational 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.
摘要
外周动脉疾病(PAD)是由外周动脉的动脉粥样硬化引起的,最常见于
西拉司妥唑是最后一种被批准用于治疗的药物,
PAD患者(1999),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;运动时疼痛,休息后缓解)或肢体危象
缺血(CLI;休息时疼痛,伴或不伴组织坏死或坏疽)。虽然比IC更不常见,但CLI
具有显著更高的发病率和死亡率; CLI患者具有大截肢或死亡的风险,
一年内接近40%。IC和CLI临床病程的差异以及最近的预处理结果
临床研究提出了有趣的可能性,即IC和CLI代表了不同的表型表现,
同样的疾病过程。我们提出了一个创新的想法:再生和功能健全的骨骼肌
支持缺血性新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。我们的提议将直接测试局部肢体缺血细胞的能力
微环境以改变组织结果。我们将探讨人BAG 3(Bcl-2相关的BAG 3)在人免疫缺陷病毒中的作用。
athanogene 3 -一种进化上保守的575个氨基酸的蛋白质),特别是在肢体肌肉中,
患者和小鼠的内皮细胞。BAG 3是一种多功能支架蛋白和共伴侣,
在心脏和骨骼肌中的多效性作用。这是一个有前途的遗传候选治疗的发展
1)BAG 3突变引起肌原纤维性肌病和扩张性肌纤维性肌病,
人类心肌病,2)BAG 3变体存在于患有CLI的非裔美国人(人口统计学)中
不成比例地受PAD影响-初步数据)和心肌病,以及3)
BAG 3调节PAD(后肢)临床前模型中的肌肉再生、血管密度和肢体存活
缺血-HLI)。为此,这项提案汇集了临床血管外科医生,骨骼肌生物学家,
他专注于生理结果测量,是一位生物化学家和线粒体生物学家,
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,
无与伦比的人类PAD组织生物库。这一建议的核心假设是,
BAG 3的变异导致肌病和肌病,
肌肉和内皮细胞,并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的联系2)确定Cox 6a 2表达是否足以挽救
BAG 3变体在PAD条件下诱导肌病。3)确定BAG 3变异体是否与AA
CLI患者结局的种族和差异。
项目成果
期刊论文数量(0)
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JOSEPH Matthew MCCLUNG其他文献
JOSEPH Matthew MCCLUNG的其他文献
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{{ truncateString('JOSEPH Matthew MCCLUNG', 18)}}的其他基金
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:
10589077 - 财政年份:2021
- 资助金额:
$ 64.87万 - 项目类别:
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:
10187852 - 财政年份:2021
- 资助金额:
$ 64.87万 - 项目类别:
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 - 财政年份:2015
- 资助金额:
$ 64.87万 - 项目类别:
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 - 财政年份:2015
- 资助金额:
$ 64.87万 - 项目类别:
Peripheral endothelial and muscle cell pathology in cardiovascular disease
心血管疾病中的外周内皮和肌肉细胞病理学
- 批准号:
8780799 - 财政年份:2013
- 资助金额:
$ 64.87万 - 项目类别:
Peripheral endothelial and muscle cell pathology in cardiovascular disease
心血管疾病中的外周内皮和肌肉细胞病理学
- 批准号:
7959104 - 财政年份:2010
- 资助金额:
$ 64.87万 - 项目类别:
Peripheral endothelial and muscle cell pathology in cardiovascular disease
心血管疾病中的外周内皮和肌肉细胞病理学
- 批准号:
8130922 - 财政年份:2010
- 资助金额:
$ 64.87万 - 项目类别:
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