Novel Transcriptional Regulators of Angiogenesis

血管生成的新型转录调节因子

• 批准号: 7425900
• 负责人: ANTONINO PASSANITI
• 金额: $ 25.59万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-19 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7425900
• 关键词: Angiogenesis Inhibition; Angiogenic Factor; Angiogenic Switch; Blood Vessels; Breast Cancer Cell; Cell Cycle; Cell Cycle Progression; Cell Line; Cell Proliferation; Cells; Condition; Cyclin-Dependent Kinase Inhibitor; DNA Binding; Data; Development; Disease; Down-Regulation; Drug Delivery Systems; Endothelial Cells; Epithelial Cell Proliferation; Exhibits; Family; Gene Expression; Genetic Transcription; Goals; Growth; Health; Lead; Lytic Metastatic Lesion; Mediating; Mission; Modeling; Molecular; Neoplasm Metastasis; Pathway interactions; Phosphorylation; Physiological; Play; Prostatic Neoplasms; Protein Binding; Public Health; Publishing; Repression; Research; Research Personnel; Role; Signal Pathway; Signal Transduction; Small Interfering RNA; Testing; Therapeutic Agents; Transforming Growth Factors; Tumor Angiogenesis; Tumor-Associated Vasculature; United States National Institutes of Health; Vascular Endothelial Cell; Work; activating transcription factor; angiogenesis; antitumor agent; bone; cancer cell; cancer therapy; improved; in vivo; member; neoplastic cell; novel; programs; promoter; protein expression; response; runx proteins; therapeutic target; transcription factor; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): Angiogenesis promotes tumor growth and metastasis and is an important therapeutic target in the treatment of cancer. Angiogenesis factors activate transcription factors that control endothelial cell proliferation. RUNX2 is a DNA-binding transcription factor that interacts with the TGFb/Smad family of transcriptional modulators to stimulate cell proliferation and tumor progression. RUNX2 also represses the promoter of p21Cip1, a cyclin-dependent kinase inhibitor, inhibits p21Cip1 protein expression, and reduces TGFb-mediated growth inhibition of endothelial cells. We hypothesize that RUNX2 stimulates angiogenesis and endothelial cell proliferation by promoting cell cycle progression through its inhibition of the TGFb1/Smad pathway and repression of p21Cip1 expression. The following specific aims will test this hypothesis. SPECIFIC AIM 1: To establish a role for RUNX2 in stimulating endothelial cell proliferation and promoting angiogenesis in vivo. SPECIFIC AIM 2: To define the requirement for RUNX2 expression and phosphorylation in controlling endothelial cell cycle progression and angiogenesis. SPECIFIC AIM 3: To determine how RUNX2 promotes cell cycle progression and EC proliferation through inhibition of the TGFb1/Smad pathway and/or the cdk inhibitor, p21Cip1. The goals of this proposal are to define how RUNX2 increases endothelial cell proliferation, to determine how RUNX2 regulates cell cycle progression, and to define the interactions of RUNX2 with Smad signaling components, which regulate p21Cip1 expression. Several molecular approaches will be employed, including siRNA-mediated knockdown of RUNX2, the use of RUNX2-inducible cell lines, and cell cycle regulatory activities of RUNX2. Angiogenesis research may uncover new mechanisms regulating blood vessel formation within tumors and could lead to identification of novel anti-tumor agents or improved drug delivery to tumors. Therefore, the development of anti-angiogenic therapeutic agents that inhibit EC proliferation is highly relevant to the NIH mission to improve public health and is a critical approach that may become important in the treatment of cancer. Although not a topic of this proposal, the strategies and treatments discovered in this study may also be relevant for the treatment of other diseases that depend on angiogenesis and cause significant health problems.

描述（申请人提供）：血管生成促进肿瘤生长和转移，是癌症治疗中的重要治疗靶点。血管生成因子激活控制内皮细胞增殖的转录因子。 RUNX2 是一种 DNA 结合转录因子，可与转录调节剂 TGFb/Smad 家族相互作用，刺激细胞增殖和肿瘤进展。 RUNX2 还抑制 p21Cip1（一种细胞周期蛋白依赖性激酶抑制剂）的启动子，抑制 p21Cip1 蛋白表达，并减少 TGFb 介导的内皮细胞生长抑制。我们假设 RUNX2 通过抑制 TGFb1/Smad 通路和抑制 p21Cip1 表达来促进细胞周期进程，从而刺激血管生成和内皮细胞增殖。以下具体目标将检验这一假设。具体目标 1：确定 RUNX2 在体内刺激内皮细胞增殖和促进血管生成中的作用。具体目标 2：确定 RUNX2 表达和磷酸化在控制内皮细胞周期进程和血管生成中的要求。具体目标 3：确定 RUNX2 如何通过抑制 TGFb1/Smad 通路和/或 cdk 抑制剂 p21Cip1 促进细胞周期进展和 EC 增殖。该提案的目标是确定 RUNX2 如何增加内皮细胞增殖，确定 RUNX2 如何调节细胞周期进程，并确定 RUNX2 与 Smad 信号成分（调节 p21Cip1 表达）的相互作用。将采用多种分子方法，包括 siRNA 介导的 RUNX2 敲低、使用 RUNX2 诱导细胞系以及 RUNX2 的细胞周期调节活性。血管生成研究可能会揭示调节肿瘤内血管形成的新机制，并可能导致新型抗肿瘤药物的鉴定或改善肿瘤的药物输送。因此，开发抑制 EC 增殖的抗血管生成治疗剂与 NIH 改善公众健康的使命高度相关，并且是可能在癌症治疗中变得重要的关键方法。尽管不是本提案的主题，但本研究中发现的策略和治疗方法也可能与依赖血管生成并导致严重健康问题的其他疾病的治疗相关。