RI COBRE: MECHANISMS OF ANGIOGENESIS IN CHONDROSARCOMA

RI COBRE：软骨肉瘤的血管生成机制

• 批准号: 8168037
• 负责人: RICHARD M TEREK
• 金额: $ 25.48万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8168037
• 关键词: Angiogenesis Inhibitors; Biology; Blood Vessels; Bone neoplasms; Cartilage; Chondrocytes; Chondrosarcoma; Computer Retrieval of Information on Scientific Projects Database; Cytotoxic Chemotherapy; Disease; Down-Regulation; Epiphysial cartilage; Equilibrium; Funding; Genetic; Goals; Grant; Growth; Hypoxia; Institution; Interstitial Collagenase; Mediating; Metastatic Neoplasm to the Lung; Molecular Target; Pathway interactions; Patients; Physiological; Regulation; Research; Research Personnel; Resistance; Resources; Role; Signal Transduction; Source; Tissue Engineering; United States National Institutes of Health; Vascular Endothelial Growth Factors; angiogenesis; antiangiogenesis therapy; base; clinical practice; human HDAC4 protein; improved; neoplastic cell; outcome forecast; response; transcription factor; treatment strategy; tumor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Chondrosarcoma is a primary bone tumor with a poor prognosis as patients with this disease develop fatal pulmonary metastases. Survival has not improved since these tumors are resistant to cytotoxic chemotherapy. Antiangiogenesis therapy is a relatively new treatment strategy yet to be tried for chondrosarcoma. Our long-term goal is to provide the groundwork for bringing this treatment into clinical practice by identifying the appropriate molecular targets. The signals that induce growth of blood vessels arise from the normal physiologic response to hypoxia, primarily regulated by hypoxia inducing factor-1 (HIF-1), and genetic aberrations in tumor cells resulting in dysregulation of the balance between pro- and antiangiogenic factors. Our overall HYPOTHESIS is that the pathway regulating chondrocyte maturation and endochondral ossification in the growth plate comprised of histone deacetylase 4 (HDAC4), runt-related transcription factor 2 (Runx2), and vascular endothelial growth factor (VEGF), is reactivated in chondrosarcoma and causes angiogenesis. Specific Aims: (1) Define the role of HDAC4 and Runx2 in the regulation of VEGF expression in chondrosarcoma and assess the biologic impact of normalizing HDAC4/Runx2 expression on angiogenesis. (2) Investigate the role of HIF-1/CXCR4/SDF1 mediated regulation of MMP-1 and VEGF. (3) Analyze the mechanism of Runx2 downregulation of p16 expression and the effect on angiogenesis. Significance: An understanding of the mechanisms of angiogenesis is a necessary first step in developing rationally based antiangiogenic treatment strategies. In addition, a better understanding of angiogenic pathways in chondrosarcoma may contribute to the overall understanding of cartilage biology, tissue engineering of cartilage, and mechanisms of angiogenesis in other tumors.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 软骨肉瘤是一种预后不良的原发性骨肿瘤，因为患有这种疾病的患者会发生致命的肺转移。 由于这些肿瘤对细胞毒性化疗具有抗性，因此生存率没有改善。 抗血管生成治疗是一种相对较新的治疗策略，尚未尝试软骨肉瘤。 我们的长期目标是通过确定适当的分子靶点，为将这种治疗方法引入临床实践提供基础。 诱导血管生长的信号来自对缺氧的正常生理反应，主要由缺氧诱导因子-1（HIF-1）调节，以及肿瘤细胞中的遗传畸变导致促血管生成因子和抗血管生成因子之间的平衡失调。 我们的总体假设是，由组蛋白脱乙酰酶4（HDAC 4）、Runx相关转录因子2（Runx 2）和血管内皮生长因子（VEGF）组成的生长板中调节软骨细胞成熟和软骨内骨化的途径在软骨肉瘤中被重新激活并引起血管生成。 具体目标：（1）确定HDAC 4和Runx 2在软骨肉瘤中VEGF表达调节中的作用，并评估HDAC 4/Runx 2表达正常化对血管生成的生物学影响。 (2)探讨HIF-1/CXCR 4/SDF 1对MMP-1和VEGF的调控作用。 (3)分析Runx 2下调p16表达的机制及对血管生成的影响。 重要性：了解血管生成的机制是发展合理的抗血管生成治疗策略的必要的第一步。 此外，更好地了解软骨肉瘤中的血管生成途径可能有助于全面了解软骨生物学，软骨组织工程和其他肿瘤中的血管生成机制。