ANALYSIS OF Id GENE TARGETS IN TUMOR ENDOTHELIAL CELLS

肿瘤内皮细胞中 Id 基因靶点分析

• 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
• 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

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合理的抗血管生成治疗策略的关键，也是一个深入研究的领域。 在过去的十年中，已经确定了几种调节关键血管生成途径的分子，但肿瘤中血管形成的分子基础仍不完全清楚。 然而，很明显，血管生成中的一些关键参与者是螺旋-环-螺旋 Id 蛋白。 我们研究的主要目标是阐明肿瘤新血管生成复杂过程中涉及的分子机制。 在成年小鼠中，转录因子 Id1 和 Id3 在肿瘤血管内皮中过度表达，但在静息血管中不表达。 Id1和Id3的缺失会导致肿瘤诱导的新血管形成的严重缺陷，并损害异种移植物和生理相关自发肿瘤的生长和转移。 因此，Id小鼠模型可用于研究与肿瘤相关的出生后新血管生成。 我们广泛的具体目标是鉴定肿瘤内皮细胞中的 Id 调节基因，确定它们在促进细胞增殖、细胞迁移以及最终肿瘤新生血管形成中的功能作用。 Id 转录靶标的鉴定和功能分析不仅将为 Id 作为转录调节剂的作用提供基本见解，而且还会影响合理的抗血管生成治疗干预措施的开发，从而破坏 Id 介导的人类肿瘤生长。