Molecular regulation and therapeutic targeting of the TSC signaling network

项目总结 癌症包括一系列以异常细胞过度增殖为特征的疾病。这个 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200多万个独特的突变。这些中的哪一个 突变是因果的，是必然的，哪些只是旁观者，这是一个继续的问题 辩论。增加困惑和不确定性的往往是关于善意的角色的相互矛盾的发现 常见癌症中的癌基因和抑癌基因。癌症不是一种单个蛋白质的疾病，而是 一种复杂的疾病，更有可能被理解为信号通路和 网络。事实上，影响重要信号中枢行为的突变，如RAS/PKA、P53和 MTOR及其相关的信号网络在许多癌症中被过度表达。理解 细胞信号通路的体系结构，识别这些通路传递的信息，以及 发现这些信息是如何以及在哪里被处理的，以告知细胞做出关于生长的决定 是理解癌症等复杂疾病的关键。 绘制单元电路的基本结构图已经开始，但仍在很大程度上等待功能数据 覆盖。这项资助提案寻求：1)通过全面剖析位于TSC上游的电路 绘制各种相关生理条件下的调控相互作用图。2)确定关联 调控位点对TSC调控模式的影响，例如本地化、Rheb-Gap活性和复杂性的变化 稳定性。3)通过询问复杂环境来建立输入信号的层次结构，这些环境具有多个 同时的刺激。4)对TSC监管的这种新的机械性理解将与已识别的 患者TSC的突变，以更深入地了解疾病过程并预测治疗机会。 5)鉴定和增敏具有TSC依赖获得性治疗耐药的癌细胞系。总而言之，这 信息将大大有助于开发针对TSC肿瘤综合征的有效靶向治疗 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.