Project 3- Role of Leukocyte-Platelet Interactions in Inflammation and Thrombosis

项目 3-白细胞-血小板相互作用在炎症和血栓形成中的作用

• 批准号: 10268699
• 负责人: Daniel I Simon
• 金额: $ 53.61万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10268699
• 关键词: Acute; Adaptive Immune System; Adhesives; Affect; African American; Arterial Injury; Arthritis; Attenuated; Autoantibodies; Autoimmune Diseases; Binding; Binding Sites; Biochemical; Biological Markers; Blood; Blood Platelets; Blood Vessels; Brain; Cardiovascular Diseases; Caucasians; Cell Adhesion; Cell Adhesion Molecules; Cells; Clinical; Cognitive; Complex; Cross-Sectional Studies; Cytoplasmic Tail; Cytotoxic agent; Deposition; Development; Disease; Disease model; Exanthema; FOXP1 gene; Fatigue; Flare; Functional disorder; Generations; Glomerulonephritis; Hair; Hemostatic function; Hispanics; IRAK1 gene; ITGAM gene; ITGB2 gene; Immune System Diseases; Immunosuppressive Agents; Impairment; Inflammasome; Inflammation; Inflammatory; Innate Immune System; Integrins; Interruption; Joints; Kidney; Laboratories; Lasers; Leukocytes; Ligand Binding; Ligation; Lung; Lupus; Macrophage-1 Antigen; Mediating; Methods; Microcirculation; Modeling; Molecular; Monoclonal Antibodies; Multiple Sclerosis; Mus; Mutant Strains Mice; Nature; Nuclear; Observational Study; Organ; Pain; Pathogenesis; Patient Agents; Patients; Peptides; Population; Prevalence; Prevention; Process; Reporting; Role; Serum; Signal Transduction; Site; Skin; Stable Disease; Stroke; Structure; Survival Rate; Symptoms; Systemic Lupus Erythematosus; Systemic disease; Talin; Therapeutic immunosuppression; Thrombosis; Time; Tissues; Vasculitis; Venous; Venous Thrombosis; Woman; base; chronic pain; experience; experimental study; extracellular; forkhead protein; health disparity; in vivo; insight; macrophage; monocyte; mouse model; neutrophil; novel; novel therapeutics; receptor; recruit; response; restenosis; therapeutically effective; thrombotic; vascular injury

PROJECT SUMMARY/ABSTRACT This translational project will focus on systemic lupus erythematosus (SLE) as a unique disease model of inflammation and thrombosis. SLE is a complex autoimmune disease. The prevalence of SLE ranges from 20 to 150 cases per 100,000 population. SLE affects primarily women and there is a significant impact of health disparities in patients with Lupus. SLE is 2-3 times more prevalent among African American and Hispanic than among Caucasian women. Patients with SLE can experience significant symptoms, such as chronic pain, extreme fatigue, hair loss, cognitive issues, and physical impairments that affect every facet of their lives. Many suffer from cardiovascular disease, strokes, disfiguring rashes, and painful arthritis. The 10-year survival rate is about 70%. Historically, SLE has been considered as an adaptive immune system disorder characterized by the presence in patient serum of autoantibodies raised against nuclear components which deposit in blood vessels, skin, kidney, lung, joints and brain causing tissue damage and clinical manifestations. New advances in the understanding of SLE pathogenesis have focused on the innate immune system, with a particular focus on leukocytes (i.e., neutrophils, monocytes) as key players in perpetuating and amplifying this systemic disease. Currently, there is no prevention or cure for SLE, and the mainstay of treatment is non-specific immunosuppressive and cytotoxic agents. Thus, there is significant unmet clinical need in SLE and compelling demand for more effective therapeutic approaches. Leukocyte-platelet interactions induce bidirectional signals that amplify pro-inflammatory and pro- thrombotic cellular responses. We have focused on the leukocyte integrin Mac-1 (αMβ2), identifying this adhesive receptor as a critical molecular determinant of leukocyte recruitment and signaling. Our laboratory first reported the interaction between Mac-1 and its platelet counter-receptor GPIbα and determined the molecular basis of GPIb recognition. We established that Mac-1:GPIbα broadly regulates inflammation in models of vasculitis, glomerulonephritis, and multiple sclerosis as well as arterial thrombosis. The central hypothesis of this proposal is that the Mac-1:GPIbα interaction is broadly required for inflammation and initiates pro-inflammatory and prothrombotic signals that promote diverse disease processes. The specific aims of the project are: 1) To determine the effect of disrupting Mac-1:GPIbα on the progression and complications of SLE using mouse models; 2) To define the physical determinants of Mac-1:GPIbα binding and the nature of “outside-in” signals generated by this interaction; and 3) To provide evidence that clinical SLE disease activity is correlated with biomarkers of the Mac-1:GPIbα interaction. Because leukocyte-platelet interactions broadly regulate inflammation and thrombosis, understanding the molecular machinery of this cellular complex will provide important insights for developing new therapies directed at reducing end-organ damage in SLE and other inflammatory/thrombotic disorders.

项目总结/摘要 这个翻译项目将集中在系统性红斑狼疮（SLE）作为一种独特的疾病模型 炎症和血栓形成SLE是一种复杂的自身免疫性疾病。SLE的患病率范围 从每10万人20例增加到150例。SLE主要影响女性， 狼疮患者的健康差异。SLE在非裔美国人中的患病率是非裔美国人的2-3倍， 西班牙裔女性多于白人女性。SLE患者可能会出现明显的症状，例如 慢性疼痛、极度疲劳、脱发、认知问题和影响各个方面的身体损伤 他们的生活。许多人患有心血管疾病、中风、毁容皮疹和疼痛的关节炎。 10年生存率约为70%。从历史上看，SLE一直被认为是一种适应性免疫， 以患者血清中存在抗核抗体为特征的一种系统疾病 存款在血管，皮肤，肾脏，肺，关节和大脑造成组织损伤的成分 和临床表现。SLE发病机制的新进展主要集中在 先天免疫系统，特别关注白细胞（即，中性粒细胞，单核细胞）作为关键参与者 使这种系统性疾病延续和扩大。目前，没有预防或治愈SLE， 治疗的主要手段是非特异性免疫抑制剂和细胞毒性剂。因此， SLE中显著未满足的临床需求和对更有效治疗方法的迫切需求。 白细胞-血小板相互作用诱导双向信号，其放大促炎性和促血小板活化作用。 血栓细胞反应。我们重点研究了白细胞整合素Mac-1（αMβ2）， 粘附受体作为白细胞募集和信号传导的关键分子决定因素。我们 实验室首次报道了Mac-1与其血小板反受体GPIbα之间的相互作用， 确定了GPIb识别的分子基础。我们确定Mac-1：GPIbα广泛调节 血管炎、肾小球肾炎和多发性硬化模型中的炎症以及动脉炎 血栓形成该建议的中心假设是Mac-1：GPIbα相互作用是广泛需要的 并启动促炎和促血栓形成信号，促进各种疾病 流程.本项目的具体目标是：1）确定干扰Mac-1：GPIbα对 使用小鼠模型研究SLE的进展和并发症; 2）确定SLE的物理决定因素， Mac-1：GPIbα结合和这种相互作用产生的“由外向内”信号的性质;以及3）提供 临床SLE疾病活动性与Mac-1：GPIbα相互作用的生物标志物相关的证据。 由于白细胞-血小板相互作用广泛地调节炎症和血栓形成， 这种细胞复合体的分子机制将为开发新疗法提供重要的见解 旨在减少SLE和其他炎性/血栓性疾病中的终末器官损伤。