The Role of IKK and NF-kappaB in Controlling mTOR Signaling and TSC Progression

描述（由申请人提供）：多发性硬化综合征（TSC）是一种人类综合征，其特征在于在包括皮肤、脑、肺、心脏和肾在内的多种器官中广泛发展良性肿瘤。TSC由TSC 1或TSC 2基因突变引起。最近的研究表明，TSC 1和TSC 2抑制哺乳动物雷帕霉素靶蛋白（mTOR）信号通路来控制细胞生长;因此，TSC 1或TSC 2基因突变导致的mTOR信号异常激活可能是TSC发病的基础。虽然与mTOR调节和mTOR下游效应相关的机制已部分表征，但关于这些机制仍有许多未知之处。重要的是，TSC的治疗是姑息性的，目前还没有有效的治愈方法。我们最近发现IKK复合物（转录因子NF-κ B的关键上游调节因子）与mTOR复合物相互作用，并显著增加mTORC 1和mTORC 2的活性。此外，我们的研究结果表明，mTOR控制IKK/NF-NF-kB激活的双重性。这些结果暗示IKK/NF-κ B通路是TSC/mTOR信号通路的新调节剂。我的数据还表明，TSC 2和雷帕霉素调节IKK/NF-κ B活性通过mTORC 1在Akt依赖性的方式。基于我发表的研究和初步数据，我假设IKK和NF-kB是mTOR和Akt在控制TSC进展中的关键调节剂和效应物，并且雷帕霉素与IKK抑制剂组合可以有效地阻断mTOR、Akt和IKK/NF-kB的活性，并最终阻断TSC动物模型中TSC的进展。我将描述IKK 1控制几种癌细胞和TSC 2-/- MEF细胞中TORC 1和mTORC 2活性的机制。我将广泛研究TSC 2和雷帕霉素与IKK抑制剂联合如何影响细胞和TSC动物模型中的NF-κ B活性和TSC进展。本研究的目的是从机制上理解IKK/NF-kB和mTOR通路在促进细胞存活和生长以及TSC进展中的相互作用。这些基因和生化分析以及动物模型研究将为TSC/mTOR和IKK/NF-kB通路的调控和功能以及TSC的进展提供新的见解。进一步的研究可能导致新的治疗靶点的鉴定，并最终帮助开发靶向TSC和TSC相关肿瘤的合理的、基于机制的治疗策略。

DESCRIPTION (provided by applicant): Tuberous sclerosis complex (TSC) is a human syndrome characterized by widespread development of benign tumors in a variety of organs including skin, brain, lung, heart and kidney. TSC is caused by mutation in either the TSC1 or TSC2 gene. Recent studies have indicated that TSC1 and TSC2 suppress the mammalian target of rapamycin (mTOR) signaling pathway to control cell growth; thus, abnormal activation of mTOR signaling as a result of mutation in TSC1 or TSC2 gene may underlie the pathogenesis of TSC. While mechanisms associated with mTOR regulation and with mTOR downstream effects have been partly characterized, much is still unknown regarding these mechanisms. Importantly, treatment of TSC is palliative and no effective cure is known. We have recently found that the IKK complex (key upstream regulator of the transcription factor NF-kB) interacts with the mTOR complex and significantly increases both mTORC1 and mTORC2 activity. Additionally, our results revealed that mTOR controls IKK/NF-NF-kB activation reciprocally. These results implicate IKK/NF- kappaB pathway as a novel regulator of TSC/mTOR signaling pathway. My data also demonstrate that both TSC2 and rapamycin regulate IKK/NF-kB activity through mTORC1 in an Akt-dependent manner. Based on my published studies and preliminary data, I hypothesize that IKK and NF-kB are critical regulators and effectors for mTOR and Akt in controlling the progression of TSC, and that rapamycin in combination with an IKK inhibitor could effectively block the activity of mTOR, Akt and IKK/NF-kB and ultimately block progression of TSC in TSC animal models. I will characterize the mechanism whereby IKK1 controls TORC1 and mTORC2 activity in several cancer cells and in TSC2 -/- MEF cells. I will extensively examine how TSC2 and rapamycin, in combination with an IKK inhibitor, affect NF-kB activity and TSC progression in cells and TSC animal models. The goal of this proposal is to achieve a mechanistic understanding of the interaction between IKK/NF-kB and mTOR pathways in promoting cell survival and growth, and progression of TSC. The proposed genetic and biochemical analyses and animal model studies will provide novel insight into the regulation and function of TSC/mTOR and IKK/NF-kB pathways, and the progression of TSC. Further studies could lead to the identification of new therapeutic targets and ultimately help develop rational, mechanism- based treatment strategies that target TSC and TSC-related tumors.