Inhibiting JNK A New Anti-Inflammatory Strategy

描述(由申请人提供)：炎症是宿主防御和组织修复所必需的过程。然而，旺盛的防御可能会导致病理性变化，导致动脉粥样硬化等血管疾病。这一更新申请的主要目标是在前一次授权的基础上，表征促炎细胞因子，如血管内皮细胞(EC)中的肿瘤坏死因子激活的信号转导，以确定炎症中新的JNK激活途径。肿瘤坏死因子的信号通路是双峰的：通过激活核因子-kappaB产生生存信号，通过激活JNK产生炎症/凋亡信号。这一建议的主要假设是，在不中断核因子-kappaB激活的情况下抑制JNK为抗炎治疗提供了一种有效的方法。我们已经确定了几个分子，包括ASK1和AlP1，它们专门介导JNK(但不是NF-kappaB)信号。此外，抗动脉粥样硬化的层流抑制了肿瘤坏死因子诱导的ASK1-JNK和促炎分子的基因表达。我们克隆了一个新的RAS-GAP蛋白(ALP1)，并证明了AlP1在肿瘤坏死因子诱导的ASK1-JNK活化中起关键作用，是动脉粥样硬化保护层流的新靶点。需要研究的具体假设是：AlP1指定TRAF2用于ASK1-JNK的激活；AlP1是预防肿瘤坏死因子诱导的ASK1-JNK激活的流量传感器。我们提出了三个特定的目标：1)确定AlP1在肿瘤坏死因子诱导的JNK通路中的作用。2)明确AlP1在血流介导的抑制肿瘤坏死因子诱导的Aski/JNK活化中的作用。3)探讨AlP1在apoE-/-小鼠动脉粥样硬化中的作用。这项提议应该提供候选蛋白质，这些蛋白质是肿瘤坏死因子介导的炎症事件的特定或独特的靶点，并促进开发新的治疗方法来控制各种疾病环境中的炎症。

DESCRIPTION (provided by applicant): Inflammation is a process essential for host defense and tissue repair. However, exuberant defense may cause pathogenic changes leading to vascular diseases such as atherosclerosis. The primary goal of this renewal application is to build from the previous granting period to characterize proinflammatory cytokines such as TNF-activated signal transduction in vascular endothelial cells (EC) to identify novel JNK activation pathways in inflammation. TNF signaling events are bimodal: survival signal via activation of NF-kappaB, inflammation/apoptosis via activation of JNK. The major hypothesis of this proposal is that inhibition of JNK without disruption of NF-kappaB activation provides a valid approach for anti-inflammatory therapy. We have identified several molecules including ASK1 and AlP1 specifically mediating JNK (but not NF-kappaB) signaling. Moreover, atheroprotective laminar flow inhibits TNF-induced ASK1-JNK and gene expression of proinflammatory molecules. We have cloned a novel Ras-GAP protein (ALP1) and demonstrated that AlP1 is critical for TNF-induced ASK1-JNK activation and is a new target of atheroprotective laminar flow. The specific hypotheses to be investigated are: AlP1 specifies TRAF2 for ASK1-JNK activation; AlP1 is a flow sensor in prevention of TNF-induced ASK1-JNK activation. Three specific aims are proposed: 1) To determine the roles of AlP1 in TNF-induced JNK pathway. 2) To define the roles of AlP1 in flow-mediated inhibition on TNF-induced ASKI/JNK activation. 3) To determine the role of AlP1 in atherosclerosis in apoE- /- mouse model. 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.