ANALYSIS OF Id GENE TARGETS IN TUMOR ENDOTHELIAL CELLS

描述（由申请人提供）：血管生成-新血管的形成对肿瘤生长和转移至关重要。阐明血管生成调控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，也是一个研究热点。在过去的十年中，已经确定了几个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然不完全清楚。然而，很明显，血管生成中的一些关键角色是螺旋-环-螺旋Id蛋白。我们的主要研究目标是阐明肿瘤新生血管生成复杂过程的分子机制。在成年小鼠中，转录因子Id1和Id3在肿瘤血管内皮中过表达，而在静息血管中不表达。Id1和Id3的缺失会导致肿瘤诱导的新生血管的严重缺陷，并损害异种移植物和生理相关的自发肿瘤的生长和转移。因此，Id小鼠模型有助于研究与肿瘤相关的出生后新生血管生成。我们广泛的具体目标是确定肿瘤内皮细胞中的Id调节基因，确定其在促进细胞增殖，细胞迁移，最终肿瘤新生血管中的功能作用。Id转录靶点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的见解，而且还将影响合理的抗血管生成治疗干预措施的发展，从而破坏Id介导的人类肿瘤生长。

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.