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MBD2 as a Target for Cancer Prevention and Treatment

MBD2作为癌症预防和治疗的靶点

基本信息

批准号：
7245006
负责人：
WILLIAM George NELSON
金额：
$ 30.7万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-06-01 至 2008-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7245006
关键词：
Address Adenomatous Polyps Alleles Animal Model Binding Biological Assay Biological Models Breast Breeding Chemicals Collection Complex CpG Islands DNA DNA Methylation DNA Modification Methylases DNA Sequence DNA methyltransferase inhibition Development Diversity Library Dose End Point Epigenetic Process Evaluation Family GSTP1 gene Gene Expression Gene Expression Profile Gene Silencing Genes Genetic Genetic Transcription Genome Hour Human Hypermethylation Immunodeficient Mouse In Vitro Injection of therapeutic agent Intestines Lead Lesion MBD2 protein Malignant Neoplasms Malignant neoplasm of liver Mediating Methods Molecular Mechanisms of Action Monitor Mus Nucleic Acid Regulatory Sequences Organ Pathway interactions Peritoneal Play Preclinical Testing Prostate Protein Binding Domain Protein Family Recombinants Reporter Repression Research Design Research Project Grants Reverse Transcriptase Polymerase Chain Reaction Role Safety Schedule Screening procedure Small Interfering RNA Solid Staging Testing Therapeutic Therapeutic Index Toxic effect Transcriptional Activation Transfection adenoma cancer cell cancer prevention gene repression glutathione S-transferase pi high throughput screening inhibitor/antagonist knock-down mRNA Expression mouse model novel pharmacophore pre-clinical prevent promoter research study small molecule tumor tumor xenograft tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Of somatic genome alterations in human solid organ cancers, only changes in DNA methylation occur consistently (>90% of cases), arise early (first appearing in preneoplastic lesions), and can be reversed (the DNA sequence remains intact). Hypermethylation of CpG island sequences, which encompass the 5' transcriptional regulatory regions of many genes, can lead to repression of gene transcription via the recruitment of 5-mCpG-binding domain (MBD) family proteins. Of the MBD family proteins, MBD2 is a very attractive target for cancer prevention and treatment: Apc Mm/+ mice, prone to intestinal tumorigenesis, develop some 10-fold fewer intestinal adenomas when bred to an Mbd2 -/- background. The therapeutic strategy to be explored in this Project features the selective targeting of the MBD2 transcriptional repression pathway. To discover small molecule MBD2 pathway inhibitors, a novel staged "highthroughput" screen will be used, featuring the CpG island of GSTP1, known to be "silenced" in prostate, breast, and liver cancers via somatic hypermethylation and MBD2-mediated repression. New "lead" compounds will then be characterized for potency and efficacy at "silenced" gene reactivation, and for therapeutic index in animal model studies of cancer prevention and treatment. The Specific Aims to be pursued are: (i) the screening of 100,000 compounds for selective activation of transcription from hypermethylated GSTP1 promoter sequences, (ii) the characterization of "lead" compounds for molecular mechanisms of action, and (iii) the evaluation of preclinical anti-cancer efficacy and toxicity in mouse models.

描述（由申请人提供）：在人类实体器官癌的体细胞基因组改变中，只有DNA甲基化的变化持续发生（>90%的病例），出现较早（首先出现在肿瘤前病变中），并且可以逆转（DNA序列保持完整）。包含许多基因的5'转录调控区的CpG岛序列的超甲基化可通过募集5-mCpG结合结构域（MBD）家族蛋白而导致基因转录的抑制。在MBD家族蛋白质中，MBD 2是癌症预防和治疗的非常有吸引力的靶标：Apc Mm/+小鼠，倾向于肠道肿瘤发生，当繁殖到Mbd 2-/-背景时，发展的肠道腺瘤减少约10倍。在该项目中探索的治疗策略的特点是选择性靶向MBD 2转录抑制途径。为了发现小分子MBD 2通路抑制剂，将使用一种新的阶段性“高通量”筛选，其特征在于已知在前列腺癌、乳腺癌和肝癌中通过体细胞超甲基化和MBD 2介导的抑制而“沉默”的GST 1的CpG岛。然后，新的“先导”化合物将被表征为在“沉默”基因再激活方面的效力和功效，以及在癌症预防和治疗的动物模型研究中的治疗指数。具体目标是：（i）筛选100，000种化合物，用于选择性激活高甲基化GSTP 1启动子序列的转录，（ii）表征“先导”化合物的分子作用机制，以及（iii）评价小鼠模型中的临床前抗癌疗效和毒性。