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

项目摘要 结节性硬化症(TSC)是一种以广泛传播为特征的人类综合征 良性肿瘤发生在多种器官，包括皮肤、脑、肺、心脏和 肾脏。TSC是由TSC1或TSC2基因突变引起的。最近的研究表明 表明TSC1和TSC2抑制雷帕霉素(MTOR)信号的哺乳动物靶点 控制细胞生长的途径；因此，mTOR信号的异常激活是由于 TSC1或TSC2基因突变可能是TSC发病的基础。虽然机械装置 与mTOR调控和mTOR下游效应相关的部分 对于这些机制，目前仍有许多未知之处。重要的是，治疗 TSC是姑息性的，目前还没有有效的治疗方法。我们最近发现IKK情结 (转录因子NF-kB的关键上游调节因子)与mTOR复合体相互作用，并 显著增加mTORC1和mTORC2的活性。此外，我们的结果显示 MTOR相互调控IKK/NF-NF-kB的激活。这些结果提示IKK/NF- KappaB通路作为一种新的TSC/mTOR信号通路调节因子。我的数据也 TSC2和雷帕霉素均通过mTORC1调节IKK/NF-kB活性 AKT依赖的方式。根据我发表的研究和初步数据，我假设 IKK和NF-kB是mTOR和Akt的关键调节者和效应者。 TSC的进展，雷帕霉素联合IKK抑制剂可以有效地 阻断mTOR、Akt和IKK/NF-：B的活性，最终阻断TSC的进展 动物模型。我将描述IKKα控制TORc1和mTORC2的机制 在几种癌细胞和TSC2-/-MEF细胞中的活性。我将深入研究TSC2如何 雷帕霉素与IKK抑制剂联合使用可影响核因子-kB活性和TSC进展 在细胞和TSC动物模型中。这项提议的目标是实现一种机械化的 了解IKK/NF-kB与mTOR信号通路在促进细胞生长中的相互作用 TSC的生存、生长和进展。拟议的遗传和生化分析 动物模型研究将为调节和功能提供新的见解。 TSC/mTOR和IKK/NF-kB通路，以及TSC的进展。进一步的研究可能会导致 以确定新的治疗靶点，并最终帮助开发合理的机制- 基于针对TSC和TSC相关肿瘤的治疗策略。

Project Abstract 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-:B and ultimately block progression of TSC in TSC animal models. I will characterize the mechanism whereby IKKα 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.