Oncogenic Notch Signaling

描述（由申请人提供）：该计划的首要目标是阐明Notch信号传导的基本特性，这些特性对癌症的发病机制至关重要。Notch信号通路可能是15种左右调节后生动物发育和组织稳态的信号通路之一，在人类疾病（包括癌症）中经常发生紊乱。Notch的致癌作用的最明显的例子是在T细胞急性淋巴细胞白血病/淋巴瘤（T-ALL）中，其中功能获得性Notchl突变是常见的。Notchl是T-ALL中令人信服的合理治疗靶点，但迄今为止用Notch抑制剂治疗T-ALL患者的尝试尚未成功。因此，很明显，如果Notch定向治疗是有效的，需要更多的基础和转化研究。考虑到这一需求，该计划的项目1和2具有互补的目标，重点是填补我们对Notchl如何激活其靶基因的基本理解中的关键空白，这些靶基因最终负责驱动T-ALL细胞的生长和存活。项目1和项目2的具体总体目标是： 1.为了确定Notchl如何调节T-ALL细胞的基因组， 2.为了确定Notchl如何调节正常胸腺细胞的基因组 导致T-ALL的Notchl突变通常导致配体非依赖性蛋白水解和受体活化，但此类突变在其他癌症中很少甚至不存在。另一方面，有大量证据表明，配体介导的Notch受体活化在肿瘤细胞群和良性基质成分（如内皮细胞和免疫细胞）中的癌症中具有重要作用。因此，了解配体如何激活Notch受体具有广泛的癌症相关性，但配体介导的Notch激活的事件的许多基本方面仍然未知。项目3将通过实现以下目标，填补现有知识的主要空白： 3.为了检验机械力是Notch受体激活的原因的假设， 4.了解配体内吞作用的分子“逻辑”，这是配体激活Notch受体所必需的事件 该计划的目标将在一个新的生物信息学核心（核心B）的支持下部分实现，该核心由Shirley Liu博士领导，Shirley Liu博士是一位在信息学方法方面具有强大背景的研究人员，以了解癌症表观遗传学。

DESCRIPTION (provided by applicant): The overarching goal of this program is to elucidate fundamental properties of Notch signaling that are central to the pathogenesis of cancer. The Notch pathway is one of perhaps 15 or so signaling pathways that regulate development and tissue homeostasis in metazoan animals and which are frequently deranged in human diseases, including cancer. The clearest example of an oncogenic role for Notch is in T cell acute lymphoblastic leukemia/lymphoma (T-ALL), in which gain-of-function Notchl mutations are common. Notchl is a compelling rational therapeutic target in T-ALL, but attempts to treat T-ALL patients with Notch inhibitors to date have been unsuccessful. Thus, it is apparent that more basic and translational research is needed if Notch-directed therapies are to be effective. With this need in mind, Projects 1 and 2 of this Program have complementary aims focused on filling critical gaps in our basic understanding of how Notchl activates its target genes, which are ultimately responsible for driving T-ALL cell growth and survival. The specific overall objectives of Project 1 and Project 2 are: 1. To determine how Notchl regulates the genomes of T-ALL cells 2. To determine how Notchl regulates the genomes of normal thymocytes The mutations in Notchl that lead to T-ALL often result in ligand-independent proteolysis and receptor activation, but such mutations are rare to non-existent in other cancers. On the other hand, there is abundant evidence that ligand-mediated Notch receptor activation has important roles in cancer, both within tumor cell populations and benign stromal elements, such as endothelial cells and immune cells. Thus, understanding how ligands activate Notch receptors has broad cancer relevance, yet many basic aspects of the events underlying ligand-mediated Notch activation remain unknown. Project 3 will address major gaps in current knowledge by pursuing the following objectives: 3. To test the hypothesis that mechanical force is responsible for Notch receptor activation 4. To understand the molecular "logic" of ligand endocytosis, an event that is essential for activation of Notch receptors by ligands The goals of the program will be reached in part with the support of a new Bioinformatics Core (Core B) led by Dr. Shirley Liu, an investigator with a strong background in informatics approaches to understanding cancer epigenetics.