ANALYSIS OF Id GENE TARGETS IN TUMOR ENDOTHELIAL CELLS

肿瘤内皮细胞中 Id 基因靶点分析

基本信息

批准号：
7356381
负责人：
Vivek Mittal
金额：
$ 16.98万
依托单位：
COLD SPRING HARBOR LABORATORY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-04-01 至 2008-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7356381
关键词：
Adult Area BHLH Protein Blood Vessels Cell Line Cell Proliferation Classification Complex DNA Binding Domain Defect Development Endothelial Cells Endothelium Event Family Gene Expression Gene Targeting Genes Genetic Models Genetic Transcription Goals Growth Helix-Turn-Helix Motifs Human In Vitro Integrins Investigation Knock-out Mammals Mediating Modality Molecular Mus Neoplasm Metastasis Neoplasms in Vascular Tissue Pathway interactions Phenotype Process Protein Overexpression Proteins RNA Interference Regulation Research Research Proposals Rest Role Therapeutic Therapeutic Intervention Tube Tumor-Derived Xenograft procedure angiogenesis base cell motility design functional genomics helix-loop-helix protein differentiation inhibitor in vivo insight loss of function member migration mouse model multidisciplinary neoplastic cell neovascularization postnatal transcription factor tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Angiogenesis-the formation of new blood vessels is critical for tumor growth and metastasis. Elucidating the precise molecular mechanisms of angiogenic regulation is key to designing rational anti-angiogenic therapeutic strategies and is an area of intense investigation. In the past decade, several molecules regulating critical angiogenic pathways were identified, yet the molecular basis of blood-vessel formation in tumors, is still incompletely understood. It is clear, however that some of the key players in angiogenesis are the helix-loop-helix Id proteins. The major goal of our research is to elucidate the molecular mechanisms involved in the complex process of neoangiogenesis in tumors. In adult mice, transcription factors Id1 and Id3 are over expressed in the endothelium of the blood vessels of tumors but not in the resting vessels. Loss of Id1 and Id3 causes severe defects in tumor-induced neovascularization and impairs growth and metastasis of both xenografts and physiologically relevant spontaneous tumors. The Id mouse model is therefore useful to study postnatal neoangiogenesis relevant to tumors. Our broad specific aims are to identify Id regulated genes in the endothelial cells of tumors, determine their functional role in promoting cell proliferation, cell migration, ultimately tumor neovascularization. The identification and functional analysis of Id transcriptional targets will not only provide fundamental insights into the role of Id as a transcription modulator, but also impact development of rational anti-angiogenic therapeutic interventions that disrupt Id-mediated tumor growth in human.

描述（由申请人提供）：血管生成 - 新血管的形成对于肿瘤生长和转移至关重要。阐明血管生成调节的精确分子机制是设计理性抗血管生成策略的关键，并且是一个深入研究的领域。在过去的十年中，确定了调节关键血管生成途径的几个分子，但是肿瘤中血管形成的分子基础仍然尚不完全了解。但是，很明显，血管生成的一些关键参与者是螺旋环螺旋ID蛋白。我们研究的主要目的是阐明参与肿瘤新血管生成过程的分子机制。在成年小鼠中，转录因子ID1和ID3在肿瘤血管的内皮中过度表达，但在静止血管中没有表达。 ID1和ID3的丧失会导致肿瘤诱导的新血管形成严重缺陷，并损害异种移植物和生理上相关的自发性肿瘤的生长和转移。因此，ID小鼠模型可用于研究与肿瘤有关的产后新血管生成。我们广泛的具体目的是鉴定肿瘤内皮细胞中ID调控的基因，确定其在促进细胞增殖，细胞迁移，最终是肿瘤新生血管的功能作用。 ID转录靶标的识别和功能分析不仅将提供对ID作为转录调节剂作用的基本见解，而且还会影响理性抗血管生成治疗干预措施的发展，从而破坏了ID介导的人类肿瘤在人类中的生长。