INHIBITING JNK, A NEW ANTI-INFLAMMATORY STRATEGY

描述(改编自《调查者摘要》)：本报告的主要目标 建议将促炎细胞因子肿瘤坏死因子和白介素1激活 血管内皮细胞(EC)识别唯一的信号转导 炎症中的肿瘤坏死因子介导的途径。炎症是一个必不可少的过程 宿主防御和组织修复。然而，防御可能会引起病原性变化。 导致动脉粥样硬化等血管疾病。肿瘤坏死因子触发生存 通过激活核因子-kappaB的信号，通过激活的炎症(和凋亡) 肯尼迪总统。这一提议的主要假设是，在没有JNK的情况下抑制JNK 阻断核因子-kappaB的激活将提供一种有效的方法 消炎疗法。我们已经阐明了不同的促炎因素 细胞因子激活独特的和常见的细胞内信号通路，如 同源脱敏(HMD)和异源脱敏 脱敏(HTD)。经肿瘤坏死因子预处理的EC对肿瘤坏死因子耐药 再刺激，但可被IL-1重新刺激为活性JNK和表达 E-选择素和反之亦然(即JNK激活和E-选择素表达显示 同源脱敏(HMD)。相比之下，抗动脉粥样硬化的层流 抑制肿瘤坏死因子和白介素1诱导的JNK和黏附分子(异源 脱敏-HTD)。我们认为HMD调节一种细胞因子特异性 炎症，而HTD调节所有细胞因子诱导的炎症。我们会 以HMD和HTD为模型解剖肿瘤坏死因子激活的JNK NF-kappaB和IL-1信号转导途径。具体的假设是 调查结果如下：1)。HMD是通过肿瘤坏死因子受体相关因子2(TRAF2)， 肿瘤坏死因子信号转导中的接头蛋白作为JNK和JNK的分叉点 核因子-kappaB。2)。HTD通过MAP激酶ASK1，这是一个汇聚点 肿瘤坏死因子和白介素1信号在EC中的表达。令人振奋的初步数据表明 在EC中过表达TRAF2可减敏肿瘤坏死因子诱导的JNK和E-选择素，并 TRAF2的特定结构域和天然切割产物发挥作用 在JNK激活中。提出了三个具体目标。1)。HMD通过TRAF2 重点研究TRAF2的独特残基、结合蛋白和切割 产品处于JNK激活状态。2)HTD通过ASK1专注于表征流程 对肿瘤坏死因子和白介素1诱导的ASK激活的影响。3)描述的角色 TRAF2和ASK1在肿瘤坏死因子诱导的小鼠炎症模型中的作用 TRAF2或ASK1进入角膜内皮。这份提案应该提供候选人 作为肿瘤坏死因子介导的炎症的特定或独特靶点的蛋白质 事件和促进开发新的治疗方法来控制 各种疾病环境中的炎症。

DESCRIPTION (Adapted from Investigator's Abstract): The primary goal of this proposal is to characterize proinflammatory cytokines TNF and IL-1 activated signal transduction in vascular endothelial cells (EC) to identify unique TNF-mediated pathways in inflammation. Inflammation is a process essential for host defense and tissue repair. However, defense may cause pathogenic changes leading to vascular diseases such as atherosclerosis. TNF triggers survival signal via activation of NF-kappaB, inflammation (and apoptosis) via activation of JFK. The major hypothesis of this proposal is that inhibition of JNK without disruption of NF-kappaB activation would provide a valid approach for anti-inflammatory therapy. We have elucidated that different proinflammatory cytokines activate unique as well as common intracellular signaling pathways as demonstrated by homologous desensitization (HMD) and heterologous desensitization (HTD). EC pre-treated with TNF become refractory to TNF restimulation but can be restimualted by IL-1 to active JNK and express E-selectin and vice versa (i.e. JNK activation and E-selectin expression show homologous desensitization - HMD). In contrast, atheroprotective laminar flow inhibits both TNF and IL-1-induced JNK and adhesion molecules (heterologous desensitization-HTD). We believe that HMD modulates a cytokine-specific inflammation, whereas HTD modulates all-cytokine-induced inflammation. We will use HMD and HTD as models to dissect TNF-activated JNK activation from NF-kappaB and from IL-1 signaling pathway. The specific hypothesis to be investigated is that: 1). HMD is via TNF receptor-associated factor 2 (TRAF2), an adaptor protein in TNF signaling as a bifurcation point for JNK and NF-kappaB. 2). HTD is via the MAP kinase kinase kinase ASK1, a convergent point of TNF and IL-1 signaling in EC. Exciting preliminary data indicate that overexpression of TRAF2 in EC desensitizes TNF-induced JNK and E-selectin, and that the specific domains and the natural cleavage products of TRAF2 play roles in JNK activation. Three specific aims are proposed. 1). HMD is via TRAF2 focusing on characterizing TRAF2 unique residues, binding proteins and cleavage products in JNK activation. 2) HTD is via ASK1 focusing on characterizing flow effect on TNF and IL-1-induced ASK lactivation. 3) Characterizing roles of TRAF2 and ASK1 in TNF-induced inflammation in murine models by gene delivery of TRAF2 or ASK1 into cornea endothelium. This proposal should provide candidate proteins that are specific or unique targets for TNF-mediated inflammatory events and facilitate development of new therapeutic approaches to control inflammation in various disease settings.