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:
    8962372
  • 负责人:
  • 金额:
    $ 37.29万
  • 依托单位:
  • 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

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.
 描述(申请人提供):外周动脉疾病(PAD)是由外周动脉的动脉粥样硬化引起的,最常见于下肢,几乎与冠状动脉疾病(CAD)一样普遍,在美国有800万至1200万人受到影响。PAD表现为间歇性跛行(IC)或严重肢体缺血(CLI),前者为经休息后缓解的劳累疼痛,后者为静息性疼痛伴或不伴组织坏死或坏疽。与IC相比,CLI并不常见,它的发病率和死亡率要高得多;CLI患者在一年内有接近40%的大截肢或死亡的风险。有证据表明,遗传差异在PAD的易感性中发挥了作用,因为近交系小鼠对后肢缺血(HLI)的反应截然不同,后肢缺血是PAD的一种模型。C57BL/6(BL6)小鼠肢体灌注恢复正常,无组织丢失,而BALB/c小鼠肢体灌注恢复较差,组织明显坏死,与临床CLI相似。在基因筛查中 高度显著的数量性状基因座(LSQ)对小鼠HLI模型肢体存活的调节作用 1)进行了鉴定。LSQ-1含有BAG3基因,Bag3是骨骼肌纤维存活和再生所必需的。初步研究表明,单一的BAG3多态在体外缺氧的骨骼肌细胞和体内的小鼠HLI模型中导致显著的表型差异。在体内,亲本BALB/c变异体BAG3Met81的表达会导致骨骼肌纤维萎缩和肢体坏死。相比之下,BL6变种BAG3Ile81通过增加治疗肌肉中的肌纤维大小和血管密度,完全修复了这些缺陷。这一建议的中心假设是,BAG3变异与肌肉存活和缺血时的组织丢失有关。为了验证这一假说,本建议的具体目的是:1)确定BAG3功能获得对肢体缺血后骨骼肌组织坏死和灌流的影响;2)确定BAG3‘S在缺血时血管效应的细胞来源;以及3)确定BAG3在缺血中的保护作用是否与自噬有关。尽管在阐明遗传因素对PAD的作用方面取得了进展,但确定调节患者对CLI的易感性的因素对于了解疾病的发病机制以及开发促进CLI和其他目前缺乏有效治疗的缺血性疾病的保肢方法至关重要。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

JOSEPH Matthew MCCLUNG其他文献

JOSEPH Matthew MCCLUNG的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ 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:
    10375535
  • 财政年份:
    2021
  • 资助金额:
    $ 37.29万
  • 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:
    10589077
  • 财政年份:
    2021
  • 资助金额:
    $ 37.29万
  • 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:
    $ 37.29万
  • 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:
    $ 37.29万
  • 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:
    $ 37.29万
  • 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:
    $ 37.29万
  • 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:
    $ 37.29万
  • 项目类别:

相似海外基金

RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
  • 批准号:
    2327346
  • 财政年份:
    2024
  • 资助金额:
    $ 37.29万
  • 项目类别:
    Standard Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
  • 批准号:
    2312555
  • 财政年份:
    2024
  • 资助金额:
    $ 37.29万
  • 项目类别:
    Standard Grant
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
  • 批准号:
    BB/Z514391/1
  • 财政年份:
    2024
  • 资助金额:
    $ 37.29万
  • 项目类别:
    Training Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
  • 批准号:
    ES/Z502595/1
  • 财政年份:
    2024
  • 资助金额:
    $ 37.29万
  • 项目类别:
    Fellowship
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
  • 批准号:
    23K24936
  • 财政年份:
    2024
  • 资助金额:
    $ 37.29万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
  • 批准号:
    ES/Z000149/1
  • 财政年份:
    2024
  • 资助金额:
    $ 37.29万
  • 项目类别:
    Research Grant
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
  • 批准号:
    2901648
  • 财政年份:
    2024
  • 资助金额:
    $ 37.29万
  • 项目类别:
    Studentship
ERI: Developing a Trust-supporting Design Framework with Affect for Human-AI Collaboration
ERI:开发一个支持信任的设计框架,影响人类与人工智能的协作
  • 批准号:
    2301846
  • 财政年份:
    2023
  • 资助金额:
    $ 37.29万
  • 项目类别:
    Standard Grant
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
  • 批准号:
    488039
  • 财政年份:
    2023
  • 资助金额:
    $ 37.29万
  • 项目类别:
    Operating Grants
How motor impairments due to neurodegenerative diseases affect masticatory movements
神经退行性疾病引起的运动障碍如何影响咀嚼运动
  • 批准号:
    23K16076
  • 财政年份:
    2023
  • 资助金额:
    $ 37.29万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了