Mechanisms of HMGB1 Release from Ischemic Muscle in Peripheral Arterial Disease

周围动脉疾病中缺血性肌肉释放 HMGB1 的机制

• 批准号: 10320365
• 负责人: Ulka Sachdev
• 金额: $ 38.82万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10320365
• 关键词: AIM2 gene; Acetylation; Acute; Affect; Amputation; Animal Model; Antirheumatic Agents; Area; Autophagocytosis; Biochemical; Blood Vessels; Blood flow; CASP1 gene; Cardiovascular system; Caspase; Cell Death; Cell Nucleus; Cell Survival; Cell membrane; Cells; Chloroquine; Chronic; Clinical Management; Cytoprotection; Data; Disease; Drug usage; Genetic; Goals; HMGB1 Protein; Harvest; Hindlimb; Human; Image; Inflammasome; Inflammation; Inflammatory; Injury; Interleukin-1; Intramuscular; Ischemia; Knock-out; Knockout Mice; Laboratories; Ligation; Link; Mediating; Modeling; Molecular; Mus; Muscle; Muscle Cells; Muscle function; Muscle satellite cell; Myoblasts; Natural regeneration; Necrosis; Nuclear; Nuclear Protein; Nutrient Depletion; Oxidation-Reduction; Pathway interactions; Patients; Pattern; Pattern recognition receptor; Perfusion; Peripheral arterial disease; Pharmaceutical Preparations; Population; Procedures; Process; Property; Publishing; Recovery; Recovery of Function; Regulation; Reporting; Research; Risk; Role; Safety; Sampling; Severity of illness; Signal Transduction; Skeletal Muscle; Specimen; Sterility; Stress; Testing; Therapeutic; Vascular Diseases; angiogenesis; base; cell injury; controlled release; design; femoral artery; immunoregulation; improved; improved outcome; in vivo; limb ischemia; limb loss; liver injury; macrophage; muscle regeneration; neovascularization; neutralizing antibody; novel; novel strategies; operation; prevent; protein activation; protein complex; receptor; regenerative; response

PROJECT SUMMARY This proposal describes the plan for Dr. Ulka Sachdev and her colleagues to investigate the regulation and expression of HMGB1, a nuclear protein and danger signal, in limb ischemia. These studies have relevance for a large portion of the population that suffers from peripheral arterial disease, or PAD. Patients with severe PAD are at risk for limb loss if procedures to improve blood flow can not be performed. These studies hope to elucidate a mechanism by which danger signals like HMGB1 can promote local regeneration of ischemic muscle. Her preliminary data has shown that HMGB1 is present in the nuclei of patients with PAD. In animal models, nuclear stores of HMGB1 can be mobilized by treating them with chloroquine, a commonly used drug. Mobilization of HMGB1 in this way occurs through activation of protein complexes called inflammasomes. While the interconnection of these pathways has been studied in inflammatory cells, it is not clear how they function in ischemic muscle. In muscle, these pathways may be protective. The first aim will characterize the role of inflammasome activation in HMGB1 release from myoblasts. Her preliminary data shows that myoblasts activate the inflammasome in response to ischemia. This aim will characterize inflammasome components that are present in myoblasts, determine which inflammasomes are activated after ischemia or nutrient depletion, and determine which inflammasome components are required for active release of HMGB1. The second aim will characterize how regulation of inflammasome-mediated HMGB1 release in muscle is regulated. The effects of chloroquine suggest that the process involves autophagy, a cell survival mechanism. This aim will characterize the cross-talk between autophagic, inflammasome pathways and HMGB1 expression in muscle. It is believed that inflammasome pathways involving caspase-1 will be protective, and will allow for regulated release of HMGB1. HMGB1 can then help promote muscle regeneration and possibly angiogenesis. In both specific aims 1 and 2, human muscle tissue from patients with peripheral arterial disease will be evaluated for inflammasome expression and function. Samples will be taken from patients with and without PAD who are undergoing operations for vascular disorders. Samples will also be taken from amputation specimens. These studies will provide important human correlates that may be important in evaluating significant pathways in PAD. Dr. Sachdev will be working with a team of experts in clinical management of PAD, imaging, muscle function and inflammasome signaling. The team may help define a new area of therapeutics for patients with arterial insufficiency.

项目摘要 这份提案描述了Ulka Sachdev博士和她的同事调查该法规的计划 以及核蛋白和危险信号HMGB 1在肢体缺血中的表达。这些研究 与大部分患有外周动脉疾病或PAD的人群相关。患者 如果不能进行改善血流的手术，严重的PAD患者有肢体丧失的风险。这些 研究希望阐明一种机制，通过这种机制，危险信号如HMGB 1可以促进局部再生， 缺血性肌肉她的初步数据表明，HMGB 1存在于PAD患者的细胞核中。在 在动物模型中，HMGB 1的核储存可以通过用氯喹（一种常见的药物）治疗来动员。 使用药物。HMGB 1以这种方式通过激活称为HMGB 1的蛋白质复合物而发生动员。 炎性小体虽然这些通路的相互联系已经在炎症细胞中进行了研究，但还没有 清楚它们在缺血肌肉中的功能。在肌肉中，这些通路可能具有保护作用。 第一个目标将表征炎性小体激活在成肌细胞释放HMGB 1中的作用。 她的初步数据显示，成肌细胞激活炎性小体以响应缺血。这一目标将 表征成肌细胞中存在的炎性体组分，确定哪些炎性体 缺血或营养耗尽后激活，并确定哪些炎性体成分是必需的， HMGB 1的释放 第二个目标将描述炎症体介导的HMGB 1在肌肉中释放的调节 是受管制的。氯喹的作用表明，这一过程涉及自噬，一种细胞存活 机制这一目标将表征自噬、炎性小体通路和细胞凋亡之间的相互作用。 HMGB 1在肌肉中的表达。据信，涉及半胱天冬酶-1的炎性体途径将被破坏。 保护性的，并将允许HMGB 1的调节释放。HMGB 1可以帮助促进肌肉再生 以及可能的血管生成。在特定目标1和2中，使用来自外周血管疾病患者的人体肌肉组织， 评价动脉疾病的炎性体表达和功能。样本将从 因血管疾病而接受手术的PAD患者和非PAD患者。样品还将 取自截肢标本这些研究将提供重要的人类相关因素， 重要的是评估PAD中的重要途径。Sachdev博士将与一个专家小组合作， PAD的临床管理、成像、肌肉功能和炎性体信号传导。团队可能会帮助 为动脉功能不全患者的治疗开辟了新的领域。

项目成果

Three cases of acute venous thromboembolism in females after vaccination for coronavirus disease 2019.

• DOI: 10.1016/j.jvsv.2021.07.009
• 发表时间: 2022-01
• 期刊: Journal of vascular surgery. Venous and lymphatic disorders
• 作者: Andraska EA;Kulkarni R;Chaudhary M;Sachdev U
• 通讯作者: Sachdev U

Symptomatic human immunodeficiency virus infection is associated with advanced presentation and perioperative mortality in patients undergoing surgery for peripheral arterial disease.

• DOI: 10.1016/j.jvs.2021.09.034
• 发表时间: 2022-04
• 期刊: Journal of vascular surgery
• 影响因子: 4.3
• 作者: Tran LM;Cong G;Eslami MH;Mailliard RB;Sachdev-Ost U
• 通讯作者: Sachdev-Ost U

Health care disparities during the COVID-19 pandemic.

• DOI: 10.1053/j.semvascsurg.2021.08.002
• 发表时间: 2021-09
• 期刊: Seminars in vascular surgery
• 影响因子: 2.5
• 作者: Andraska EA;Alabi O;Dorsey C;Erben Y;Velazquez G;Franco-Mesa C;Sachdev U
• 通讯作者: Sachdev U

Fibrosis Distinguishes Critical Limb Ischemia Patients from Claudicants in a Transcriptomic and Histologic Analysis.

• DOI: 10.3390/jcm9123974
• 发表时间: 2020-12-08
• 期刊: Journal of clinical medicine
• 影响因子: 3.9
• 作者: Cong G;Cui X;Ferrari R;Pipinos II;Casale GP;Chattopadhyay A;Sachdev U
• 通讯作者: Sachdev U

Attenuated cell-cycle division protein 2 and elevated mitotic roles of polo-like kinase 1 characterize deficient myoblast fusion in peripheral arterial disease.

• DOI: 10.1016/j.bbrc.2022.03.161
• 发表时间: 2022-06-18
• 期刊: BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
• 影响因子: 3.1
• 作者: Ferrari, Ricardo;Cong, Guangzhi;Chattopadhyay, Ansuman;Xie, B.;Assaf, E.;Morder, K.;Calderon, Michael J.;Watkins, Simon C.;Sachdev, Ulka
• 通讯作者: Sachdev, Ulka