Novel Transcriptional Regulators of Angiogenesis

血管生成的新型转录调节因子

基本信息

批准号：
7623500
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
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-07-19 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7623500
关键词：
Angiogenesis Inhibition Angiogenic Factor Angiogenic Switch Blood Vessels Breast Cancer Cell Cell Cycle Cell Cycle Progression Cell Line Cell Proliferation Cells 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 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 neovasculature novel programs promoter protein expression response runx proteins therapeutic target transcription factor treatment strategy tumor tumor growth tumor progression

项目摘要

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（由申请人提供）：血管生成促进肿瘤的生长和转移，是癌症治疗的重要治疗靶标。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，它与转录调节剂的TGFB/SMAD家族相互作用，以刺激细胞增殖和肿瘤进展。 RUNX2还抑制了依赖细胞周期蛋白依赖性激酶抑制剂P21CIP1的启动子，抑制P21CIP1蛋白的表达，并降低TGFB介导的内皮细胞的生长抑制作用。我们假设RUNX2通过抑制TGFB1/SMAD途径并抑制P21CIP1表达来促进细胞周期的进展，从而刺激血管生成和内皮细胞增殖。以下特定目标将检验这一假设。特定目的1：确定runx2在刺激内皮细胞增殖和促进体内血管生成中的作用。特定目的2：定义对控制内皮细胞周期进程和血管生成的RUNX2表达和磷酸化的需求。特定目标3：确定RUNX2如何通过抑制TGFB1/SMAD途径和/或CDK抑制剂P21CIP1来促进细胞周期的进程和EC增殖。该提案的目标是定义Runx2如何增加内皮细胞增殖，确定Runx2如何调节细胞周期进程，并定义Runx2与SMAD信号分量的相互作用，从而调节P21CIP1表达。将采用几种分子方法，包括siRNA介导的runx2敲低，使用Runx2诱导的细胞系和Runx2的细胞周期调节活性。血管生成研究可能会发现调节肿瘤内血管形成的新机制，并可能导致鉴定出新型抗肿瘤剂或改善药物向肿瘤的递送。因此，抑制EC增殖的抗血管生成治疗剂的发展与NIH的使命高度相关，以改善公共卫生，并且是一种至关重要的方法，可能对治疗癌症变得重要。尽管这不是该提案的话题，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引起重大健康问题的其他疾病的治疗有关。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A quantitative assay to study protein:DNA interactions, discover transcriptional regulators of gene expression, and identify novel anti-tumor agents.

一种定量分析，用于研究蛋白质：DNA 相互作用、发现基因表达的转录调节因子以及鉴定新型抗肿瘤药物。

DOI：
10.3791/50512
发表时间：
2013
期刊：
Journal of visualized experiments : JoVE
影响因子：
0
作者：
Underwood,KarenF;Mochin,MariaT;Brusgard,JessicaL;Choe,Moran;Gnatt,Avi;Passaniti,Antonino
通讯作者：
Passaniti,Antonino

Roles of RUNX in Hippo Pathway Signaling.