The Role of Gab2 Signaling in Thromboinflammation

Gab2 信号传导在血栓炎症中的作用

基本信息

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
项目类别：
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

项目摘要

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.

炎症是生物体对抗入侵病原体或内源性危险的保护性反应然而，当反应不受控制时，就会导致组织损伤和有助于多种疾病的发病机制，例如类风湿性关节炎、神经退行性疾病、最近的研究强烈表明炎症过程在其中起着至关重要的作用。静脉血栓栓塞（VTE）的发病机制虽然是由信号通路激活的。炎症介质已被广泛研究，但我们对细胞如何发挥作用的理解仍然存在关键差距暴露于各种炎症刺激下，整合来自不同受体的信号以激活共同的下游刺激转录因子（如 NF-kB 和 AP-1）并诱导表达的信号通路促炎细胞粘附分子、细胞因子、Toll 样促凝血因子的激活。受体 (TLR)、肿瘤坏死因子 (TNF) 和白细胞介素 1 (IL-1) 受体通过其配体触发形成包括许多支架蛋白的多亚基信号复合物。受体结合蛋白 2 (Grb2) 相关结合蛋白 2) 是一种支架接头蛋白，可整合和放大来自多种细胞外刺激的信号，包括生长因子、抗原受体和细胞然而，Gab2 在过敏、癌症和造血中发挥着关键作用。迄今为止，Gab2 在炎症信号传导中的作用尚不清楚。我们的初步研究表明 Gab2 沉默。减弱 TNFα、IL-1β 和 LPS 诱导的细胞粘附分子、细胞因子和促凝血剂的表达研究发现，内皮细胞中的辅因子、组织因子 Gab2 沉默可减弱 NF- 的激活。我们勇敢地承认 Gab2 在 TNFR1、IL-1R1 和 TLR4 介导中发挥着核心作用。内皮细胞中的炎症信号传导途径，Gab2依赖性信号传导有助于在目标 1 中，我们将阐明 Gab2 传递 TNFR1-、IL-1R1-、和 TLR4 介导的内皮细胞信号传导，包括 Gab2 介导的结构要求 TNFR1、IL-1R1 和 TLR4 介导的信号转导及其 TAK1（TGF-β 激活激酶 1）的激活，转录因子 NF-κB 和 AP-1 的关键调节剂在目标 2 中，我们将确定 Gab2 的作用。使用 Gab2 缺陷小鼠和野生型同窝小鼠研究脓毒症中的炎症信号传导以及 VTE 的发病机制影响：确立 Gab2 作为炎症信号传导的关键角色并阐明其机制。 Gab2如何整合和传递不同炎症信号通路诱导的信号的基础我们的数据将导致关于 Gab2 在先天免疫和炎症中的作用的新的、令人兴奋的研究。研究将为设计治疗炎症性疾病的新的有效疗法提供新的见解。