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

基本信息

批准号：
10471914
负责人：
Daniel I Simon
金额：
$ 56.35万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
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：
2021-09-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10471914
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 Hispanic 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

项目摘要

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 SLE 是一种复杂的自身免疫性疾病。每 10 万人中有 20 至 150 例 SLE 主要影响女性，影响重大。系统性红斑狼疮 (SLE) 患者的健康差异在非裔美国人和白人中的患病率高出 2-3 倍。西班牙裔女性比白人女性更容易出现明显的症状，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许多人患有心血管疾病、中风、毁容性皮疹和疼痛性关节炎。历史上，SLE 被认为是一种适应性免疫，10 年生存率约为 70%。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、肺、关节并引起脑组织损伤的成分 SLE 发病机制的新进展集中在 SLE 发病机制和临床表现上。先天免疫系统，特别关注白细胞（即中性粒细胞、单核细胞）作为关键参与者目前，系统性红斑狼疮尚无预防或治愈方法。治疗的主要方法是非特异性免疫抑制剂和细胞毒药物。 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我们重点关注白细胞整合素 Mac-1 (αMβ2)，并确定了这一点。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。实验室首次报道Mac-1与其血小板反受体GPIbα之间的相互作用我们确定了 GPIb 识别的分子基础，确定 Mac-1:GPIbα 具有广泛的调节作用。血管炎、肾小球肾炎、多发性硬化症以及动脉模型中的炎症该提议的中心假设是 Mac-1:GPIbα 相互作用是广泛需要的。针对炎症并启动促炎和促血栓信号，从而促进多种疾病该项目的具体目标是： 1) 确定破坏 Mac-1:GPIbα 对的影响。使用小鼠模型研究 SLE 的进展和并发症；2) 定义 SLE 的物理决定因素 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；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。