Oncogenic Notch Signaling

致癌Notch信号

基本信息

批准号：
8895844
负责人：
JON C. ASTER
金额：
$ 101.33万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-18 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8895844
关键词：
Achievement Acute Acute T Cell Leukemia Address Adolescent Adult Affect Age Alleles Animals Automobile Driving Basic Science Benign Bioinformatics Cell Nucleus Cell Survival Cells Child Development Disease Elements Endocytosis Endothelial Cells Environment Epigenetic Process Event Gene Targeting Genetic Transcription Genome Goals Goblet Cells Homeostasis Human Immune Informatics Institution Integral Membrane Protein Intestines Knowledge Lead Ligands Logic Malignant Neoplasms Measurable Mechanics Mediating Metaplasia Mind Molecular Mus Mutation Nature Oncogenic Outcome Pathogenesis Pathway interactions Patients Population Property Proteolysis Receptor Activation Recurrent disease Refractory Refractory Disease Relapse Research Research Personnel Role Signal Pathway Signal Transduction T-Lymphocyte Testing Tissues Toxic effect Translational Research base cell growth design experience gain of function gain of function mutation human disease inhibitor/antagonist leukemia/lymphoma meetings neoplastic cell notch protein older patient outcome forecast programs response therapeutic target thymocyte tumor

项目摘要

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.

描述（由申请人提供）：该程序的总体目标是阐明对癌症发病机理至关重要的Notch信号的基本特性。 Notch途径是可能15个左右的信号通路之一，可以调节后生动物中的发育和组织稳态，并且在包括癌症在内的人类疾病中经常危险。 Notch致癌作用的最清晰的例子是在T细胞急性淋巴细胞白血病/淋巴瘤（T-ALL）中，其中功能获得的Notchl突变很常见。 NOTCHL是T-All中令人信服的理性治疗靶标，但是迄今为止，试图治疗T-All Notch抑制剂患者的尝试并未成功。因此，很明显，如果有效的疗法是有效的，则需要更基础和翻译研究。考虑到这一需求，该计划的项目1和2的互补旨在填补我们对Notchl如何激活其目标基因的基本理解的关键空白，这最终是促进T-ALL细胞生长和生存的原因。项目1和项目2的特定总体目标是： 1。确定Notchl如何调节T-ALL细胞的基因组 2。确定Notchl如何调节正常胸腺细胞的基因组导致T-all的Notchl突变通常会导致非配体依赖性蛋白水解和受体激活，但是这种突变在其他癌症中很少存在。另一方面，有大量证据表明，配体介导的Notch受体激活在癌症中，在肿瘤细胞群和良性基质元素（例如内皮细胞和免疫细胞）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，但是配体介导的Notch激活的事件的许多基本方面尚不清楚。项目3将通过追求以下目标来解决当前知识的主要差距： 3。检验机械力负责缺口受体激活的假设 4。了解配体内吞作用的分子“逻辑”，这对于通过配体激活Notch受体至关重要的事件该计划的目标将在由新的生物信息学核心（核心B）的支持下，由李·刘（Shirley Liu）博士（Core B）的支持，该研究人员在了解癌症表观遗传学方面具有强大的信息学方法背景。