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致病性变化，导致血管疾病，如动脉粥样硬化。此次更新申请的主要目标是在先前授权期的基础上建立，以表征促炎细胞因子，如血管内皮细胞（EC）中TNF激活的信号转导，以识别炎症中的新型JNK激活途径。TNF信号传导事件是双峰的：通过激活NF-κ B的存活信号，通过激活JNK的炎症/凋亡。该建议的主要假设是，抑制JNK而不破坏NF-κ B活化为抗炎治疗提供了有效的方法。我们已经鉴定了几种分子，包括特异性介导JNK（但不是NF-κ B）信号传导的ASK 1和AlP 1。此外，动脉粥样硬化保护层流抑制TNF诱导的ASK 1-JNK和促炎分子的基因表达。我们克隆了一种新的Ras GAP蛋白（ALP 1），并证明了ALP 1对TNF诱导的ASK 1-JNK激活至关重要，是动脉粥样硬化保护层流的新靶点。待研究的具体假设是：AlP 1指定TRAF 2用于ASK 1-JNK激活; AlP 1是阻止TNF诱导的ASK 1-JNK激活的流量传感器。本研究的主要目的有三：1）研究AlP 1在TNF诱导的JNK通路中的作用。2)明确AlP 1在TNF诱导的ASKI/JNK激活的血流介导的抑制中的作用。3)探讨AlP 1在apoE- /-小鼠动脉粥样硬化中的作用。这一建议应提供候选蛋白，特异性或独特的目标，肿瘤坏死因子介导的炎症事件，并促进发展新的治疗方法，以控制炎症在各种疾病的设置。

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.