Oncogenic Notch Signaling

描述(由申请人提供)：这个项目的首要目标是阐明Notch信号的基本性质，这是癌症发病机制的核心。Notch通路是调节后生动物发育和组织动态平衡的大约15个信号通路之一，在包括癌症在内的人类疾病中经常出现错乱。Notch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，功能获得Notch1突变是常见的。Notchl是T-ALL令人信服的合理治疗靶点，但使用Notch抑制剂治疗T-ALL患者的尝试迄今尚未成功。因此，很明显，如果诺奇指导的治疗要有效，就需要更多的基础和转化性研究。考虑到这一需求，该计划的项目1和2具有互补的目标，侧重于填补我们对Notchl如何激活其目标基因的基本理解中的关键空白，这些基因最终负责推动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.确定Notchl对T-ALL细胞基因组的调节作用 2.确定Notchl如何调节正常胸腺细胞的基因组 导致T-ALL的Notchl突变通常会导致配体无关的蛋白分解和受体激活，但这种突变在其他癌症中很少见甚至不存在。另一方面，有大量证据表明，配体介导的Notch受体激活在肿瘤细胞群和良性间质成分(如内皮细胞和免疫细胞)中都发挥着重要作用。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激活背后的许多基本事件仍不清楚。项目3将通过实现以下目标来解决当前知识方面的主要差距： 3.检验机械作用力导致Notch受体激活的假设 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定程度上得到一个新的生物信息学核心(核心B)的支持，该核心由雪莉·刘博士领导，她是一名研究人员，在了解癌症表观遗传学的信息学方法方面具有很强的背景。

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.