The Role of Gab2 Signaling in Thromboinflammation

Gab2 信号传导在血栓炎症中的作用

• 批准号: 10448670
• 负责人: Vijaya Mohan Rao Lella
• 金额: $ 18.38万
• 依托单位: UNIVERSITY OF TEXAS HLTH CTR AT TYLER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-10 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10448670
• 关键词: Adaptor Signaling Protein; Antigen Receptors; Arteriosclerosis; Attenuated; Binding; Binding Proteins; Binding Sites; Biology; Blood Coagulation Disorders; Blood Coagulation Factor; Blood Vessels; CCL2 gene; Cell Adhesion Molecules; Cell Surface Receptors; Cell membrane; Cells; Complex; Cytoplasmic Tail; Data; Deep Vein Thrombosis; Disease; Docking; Endothelial Cells; Endothelium; Event; Exposure to; Family; Functional disorder; Growth Factor; Heart Diseases; Hematopoiesis; Hypersensitivity; ICAM1 gene; IL8 gene; Immune; Inflammation; Inflammation Mediators; Inflammatory; Interferons; Interleukin-1 Receptors; Interleukin-1 beta; Interleukin-6; Invaded; Knowledge; Lead; Leukocytes; Ligands; MAP Kinase Gene; MAP3K7 gene; MAPK3 gene; MAPK8 gene; Malignant Neoplasms; Manuscripts; Mediating; Molecular; Mus; Myeloid Cells; NF-kappa B; Natural Immunity; Neurodegenerative Disorders; Organism; PH Domain; PTPN11 gene; Pathogenesis; Pathway interactions; Phosphatidylinositol Phosphates; Phosphatidylinositols; Phosphotransferases; Play; Process; Protein Tyrosine Phosphatase; Proteins; Publishing; Pulmonary Embolism; Research; Rheumatoid Arthritis; Role; SH3 Domains; Scaffolding Protein; Sepsis; Signal Pathway; Signal Transduction; Signaling Protein; Small Interfering RNA; Stimulus; Stroke; TLR4 gene; TNF gene; TNFRSF1A gene; Therapeutic; Thromboplastin; Thrombosis; Time; Tissues; Toll-like receptors; Transcription Factor AP-1; Transforming Growth Factor beta; attenuation; cell injury; chemokine; cofactor; cytokine; design; effective therapy; extracellular; fight against; growth factor receptor-bound protein 2; immunothrombosis; insight; knock-down; member; novel; novel therapeutics; p38 Mitogen Activated Protein Kinase; pathogen; phospholipase C gamma; prevent; receptor; receptor-mediated signaling; recruit; response; scaffold; src Homology Region 2 Domain; thromboinflammation; transcription factor; venous thromboembolism

Inflammation is a protective response of the organism to fight against invading pathogens or endogenous danger signals such as damaged cells. However, when the response goes unchecked, it results in tissue damage and contributes to the pathogenesis of various diseases such as rheumatoid arthritis, neurodegenerative diseases, heart diseases, and stroke. Recent studies strongly indicate that Inflammatory processes play a crucial role in the pathogenesis of venous thromboembolism (VTE). Although the signaling pathways activated by the inflammatory mediators have been extensively studied, still key gaps exist in our understanding of how cells exposed to various inflammatory stimuli integrate signals from diverse receptors to activate common downstream signaling pathways to stimulate transcription factors such as NF-kB and AP-1 and induce the expression of proinflammatory cell adhesion molecules, cytokines, procoagulant clotting factors. Activation of Toll-like receptors (TLRs), tumor necrosis factor (TNF), and interleukin 1 (IL-1) receptors by their ligands triggers the formation of multi-subunit signaling complexes that include many scaffolding proteins. Gab2 (growth factor receptor-bound protein 2 (Grb2)-associated binding protein 2) is a scaffolding adapter protein that integrates and amplifies signals from a wide variety of extracellular stimuli, including growth factors, antigen receptors, and cell adhesion molecules. Gab2 is shown to play a critical role in allergy, cancer, and hematopoiesis. However, to date, the role of Gab2 in inflammatory signaling is unknown. Our preliminary studies show that Gab2 silencing attenuates TNFα-, IL-1β-, and LPS- induced expression of cell adhesion molecules, cytokines, and procoagulant cofactor, tissue factor in endothelial cells. Gab2 silencing has been found to attenuate the activation of the NF- κB and MAPKs. We hypothesize that Gab2 plays a central role in TNFR1-, IL-1R1-, and TLR4- mediated inflammatory signaling pathways in endothelial cells, and Gab2-dependent signaling contributes to the pathogenesis of VTE. In Aim 1, we will elucidate the mechanism by which Gab2 transmits TNFR1-, IL-1R1-, and TLR4-mediated signaling in endothelial cells, including the structural requirements of Gab2 in mediating TNFR1-, IL-1R1, and TLR4-mediated signal transduction and its activation of TAK1 (TGF-β-activated kinase 1), a key modulator of transcription factors NF-κB and AP-1. In Aim 2, we will determine the role of Gab2 inflammatory signaling in sepsis and the pathogenesis of VTE using Gab2-deficient mice and wild-type littermate controls. Impact: Establishing Gab2 as a crucial player in inflammatory signaling and elucidating the mechanism underlying how Gab2 integrates and transmits signals induced by different inflammatory signaling pathways would lead to new and exciting research on Gab2’s role in innate immunity and inflammation. Data from our studies will provide novel insights for designing new and effective therapies to treat inflammatory disorders.

炎症是机体对抗入侵病原体或内源性危险的一种保护性反应