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.

项目概要/摘要 该转化项目将重点关注系统性红斑狼疮（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 患病率范围 每 10 万人中有 20 至 150 例病例。 SLE 主要影响女性且影响重大 狼疮患者的健康差异。 SLE 在非洲裔美国人中的患病率是其 2-3 倍 西班牙裔女性高于白人女性。 SLE 患者可能会出现明显的症状，例如 影响各个方面的慢性疼痛、极度疲劳、脱发、认知问题和身体损伤 他们的生活。许多人患有心血管疾病、中风、毁容皮疹和疼痛性关节炎。 10年生存率约为70%。历史上，SLE 被认为是一种适应性免疫 系统疾病，其特征是患者血清中存在针对核的自身抗体 沉积在血管、皮肤、肾脏、肺、关节和大脑中的成分，导致组织损伤 和临床表现。 SLE 发病机制认识的新进展集中在 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 使这种系统性疾病持续存在并扩大。目前，SLE 尚无预防或治疗方法，并且 主要治疗方法是非特异性免疫抑制剂和细胞毒药物。因此，有 SLE 的临床需求尚未得到满足，并且迫切需要更有效的治疗方法。 白细胞-血小板相互作用诱导双向信号，放大促炎和促炎症反应 血栓细胞反应。我们重点关注白细胞整合素 Mac-1 (αMβ2)，确定了这一点 粘附受体作为白细胞募集和信号转导的关键分子决定因素。我们的 实验室首次报道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、多发性硬化症以及动脉模型中的炎症 血栓形成。该提案的中心假设是广泛需要 Mac-1:GPIbα 相互作用 针对炎症并启动促炎和促血栓信号，从而促进多种疾病 流程。该项目的具体目标是： 1) 确定破坏 Mac-1:GPIbα 对 使用小鼠模型研究 SLE 的进展和并发症； 2) 定义物理决定因素 Mac-1：GPIbα 结合以及这种相互作用产生的“由外向内”信号的性质； 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调节炎症和血栓形成，因此了解 这种细胞复合物的分子机制将为开发新疗法提供重要见解 旨在减少系统性红斑狼疮和其他炎症/血栓性疾病的终末器官损伤。