The Role of Gab2 Signaling in Thromboinflammation

炎症是机体抵抗入侵病原体或内源性危险的保护性反应。 信号，如受损的细胞。然而，当反应不受控制时，它会导致组织损伤和 有助于各种疾病的发病，如类风湿性关节炎、神经退行性疾病、 心脏病和中风。最近的研究有力地表明，炎症过程在 静脉血栓栓塞症的发病机制。尽管被激活的信号通路 炎症介质已经被广泛研究，但在我们对细胞如何 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 刺激核因子-kB和AP-1等转录因子并诱导其表达的信号通路 促炎症细胞黏附分子，细胞因子，促凝血剂凝血因子。类通行费的激活 受体(TLR)、肿瘤坏死因子(TNF)和白介素1(IL-1)受体通过其配体触发 形成包含许多支架蛋白的多亚基信号复合体。GAB2(生长因子 受体结合蛋白2(Grb2)相关结合蛋白2是一种支架适配蛋白，整合了 放大来自各种细胞外刺激的信号，包括生长因子、抗原受体和细胞 黏附分子。研究表明，Gab2在过敏、癌症和造血中起着关键作用。然而，为了 目前，gb2在炎症信号转导中的作用尚不清楚。我们的初步研究表明，Gab2沉默 减轻肿瘤坏死因子α、白介素1β和脂多糖诱导的细胞黏附分子、细胞因子和促凝剂的表达 内皮细胞中的辅因子、组织因子。已经发现，沉默Gab2可以减弱核因子-2的激活。 κB和MAPKs。我们假设Gab2在TNFR1、IL-1R1和TLR4介导的过程中起核心作用 内皮细胞中的炎症信号通路，以及Gab2依赖的信号通路参与了 VTE的发病机制。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转导，包括Gab2在介导中的结构要求 肿瘤坏死因子受体1、IL-1R1和TLR4介导的信号转导及其激活转化生长因子-β活化蛋白1， 转录因子NF-κB和AP-1的关键调节因子。在目标2中，我们将确定Gab2的角色 利用Gab2基因缺陷小鼠和野生型小鼠的脓毒症炎症信号和VTE的发病机制 控制。影响：确定Gab2在炎症信号转导中起关键作用并阐明其机制 Gab2如何整合和传递不同炎症信号通路诱导的信号 这将导致对gb2的S在先天免疫和炎症中的作用的新的和令人兴奋的研究。数据来自我们的 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。

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.