Molecular regulation and therapeutic targeting of the TSC signaling network

项目摘要 癌症包括以异常细胞过度增殖为特征的疾病的集合。的 疾病可以折磨身体的所有组织和几乎每一种细胞类型，几十年的研究已经编目 超过28，000个基因在人类癌细胞中含有超过200万个独特的突变。哪些 突变是因果的，是后果的，只是旁观者，是一个持续的问题。 辩论增加混乱和不确定性的是，善意的作用往往是相互矛盾的结果， 癌基因和肿瘤抑制因子。癌症不是单个蛋白质的疾病， 这是一种复杂的疾病，更有可能被理解为信号通路的故障， 网络.事实上，影响重要信号中枢行为的突变，如Ras/PKA，p53和p53， mTOR及其相关的信号网络在许多癌症中被发现过度表达。理解 细胞信号通路的结构，识别这些通路传递的信息， 发现这些信息是如何以及在哪里被处理的，以告知细胞关于生长的决定 是理解复杂疾病如癌症的关键 绘制细胞电路的基本结构已经开始，但仍在很大程度上等待功能数据 覆盖。这项拨款建议旨在：1）全面剖析TSC上游的电路， 绘制各种相关生理条件下的调节相互作用。2)相关识别 调节位点与TSC调节模式的关系，如定位、Rheb-GAP活性和复合物的变化。 稳定3)通过询问复杂的环境，建立输入信号的层次结构， 同时刺激。4)这种对TSC调节的新的机械理解将与确定的 患者TSC突变，以更深入地了解疾病过程并预测治疗机会。 5)鉴定和敏化具有TSC依赖性获得性治疗抗性的癌细胞系。在一起，这 这些信息将大大有助于开发针对TSC肿瘤综合征的有效靶向疗法 和癌症

PROJECT SUMMARY Cancer encompasses a collection of diseases characterized by over-proliferation of abnormal cells. The disease can afflict all tissues and almost every cell type in the body, and decades of research have catalogued more than 28,000 genes harboring over 2 million unique mutations in human cancer cells. Which of these mutations are causal, which are consequential, and which are simply bystanders is a matter of continued debate. Adding to the confusion and uncertainty are often contradictory findings for the roles of bona fide oncogenes and tumor-suppressors in common cancers. Rather than a disease of individual proteins, cancer is a complex disease that is more likely to be understood as the malfunctioning of signaling pathways and networks. Indeed, mutations affecting the behavior of important signaling hubs, such as Ras/PKA, p53, and mTOR, and their associated signaling networks, are found overrepresented in many cancers. Understanding the architecture of the cell's signaling pathways, identifying the information these pathways transmit, and discovering how and where this information is processed to inform the decisions cells make regarding growth are the key to making sense of complex diseases such as cancer. Mapping the basic structure of the cell's circuitry has already begun but still largely awaits a functional data overlay. This grant proposal seeks to: 1) Dissect the circuitry lying upstream of TSC by comprehensively mapping regulatory interactions under a variety of relevant physiological conditions. 2) Relate identified regulatory sites to modes of TSC regulation, such as changes in localization, Rheb-GAP activity, and complex stability. 3) Establish the hierarchy of input signals by interrogating complex environments, those with multiple simultaneous stimuli. 4) This new mechanistic understanding of TSC regulation will be combined with identified patient mutations in TSC to gain deeper insight into the disease process and predict therapeutic oppertunities. 5) Identify and sensitize cancer cell lines with TSC dependent acquired therapeutic resistance. Together, this information will significantly aid the development of effective targeted therapies against TSC tumor syndromes and cancer.