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

项目摘要 多发性硬化症（TSC）是一种人类综合征，其特征在于广泛的 在包括皮肤、脑、肺、心脏在内的多种器官中发展良性肿瘤， 肾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）信号传导 因此，作为细胞生长的结果，mTOR信号传导的异常激活 TSC 1或TSC 2基因突变可能是TSC发病的基础。虽然机制 与mTOR调节和mTOR下游效应相关的部分 尽管这些机制已经被描述，但仍有许多关于这些机制的未知之处。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复合体 (key转录因子NF-κ B的上游调节子）与mTOR复合物相互作用， 显著增加mTORC 1和mTORC 2活性。此外，我们的结果显示， mTOR调控IKK/NF-NF-kB的活化。这些结果暗示IKK/NF- kappaB通路作为TSC/mTOR信号通路的新调节剂。我的数据也 证明TSC 2和雷帕霉素都通过mTORC 1调节IKK/NF-κ B活性， 依赖Akt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在控制细胞凋亡中的关键调节因子和效应因子。 TSC的进展，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-：B的活性，并最终阻断TSC在TSC中的进展 动物模型我将描述IKKα控制TORC 1和mTORC 2的机制 在几种癌细胞和TSC 2-/- MEF细胞中的活性。我将深入研究TSC 2 和雷帕霉素与IKK抑制剂联合影响NF-κ B活性和TSC进展 在细胞和TSC动物模型中。该提案的目标是实现一种机械化的 了解IKK/NF-kB和mTOR通路在促进细胞凋亡中的相互作用 TSC的存活和生长以及进展。建议的遗传和生化分析 动物模型的研究将提供新的见解的调节和功能， 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 识别新的治疗靶点，并最终帮助开发合理的机制- 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.