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/文摘