RI COBRE: MECHANISMS OF ANGIOGENESIS IN CHONDROSARCOMA

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，大多数患者发生致命的肺转移。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，尚未尝试用于软骨肉瘤。我们的长期目标是为将这种治疗方法引入临床提供基础 通过识别适当的分子靶点进行练习。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。我们的假设是基于初步数据，显示软骨肉瘤细胞中HDAC 4的缺失导致Runx 2和VEGF表达增加。此外，已经鉴定了转录因子Runx 2的新靶点：p16，其被Runx 2下调。p16蛋白抑制VEGF表达，而Runx 2上调VEGF。因此，Runx 2表达的增加直接和间接地通过减少p16来增加VEGF。拟议的实验利用综合分子方法来研究HDAC 4、Runx 2、p16和HIF-1相互作用最终驱动软骨肉瘤血管生成的机制。 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)研究HIF-1介导的VEGF调节和Runx 2调节VEGF之间的相互作用。 (3)分析Runx 2下调p16表达的机制及对血管生成的影响。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;这最终可能对血管生成的命运产生重大影响。 软骨肉瘤患者。

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 dismal prognosis; most 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. Our hypothesis is based on preliminary data showing that loss of HDAC4 in Chondrosarcoma cells results in increased Runx2 and VEGF expression. Furthermore, a new target of the transcription factor Runx2 has been identified: p16, which is downregulated by Runx2. The p16 protein inhibits VEGF expression, whereas Runx2 upregulates VEGF. Thus, increased Runx2 expression increases VEGF directly and indirectly through decreased p16. The proposed experiments utilize an integrative molecular approach to study the mechanisms by which HDAC4, Runx2, p16, and HIF-1 interact to ultimately drive angiogenesis in Chondrosarcoma. 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 cross-talk between HIF-1 mediated regulation of VEGF and Runx2 regulation of VEGF. (3) Analyze the mechanism of Runx2 downregulation of p16 expression and the effect on angiogenesis. An understanding of the mechanisms of angiogenesis is a necessary first step in developing rationally based antiangiogenic treatment strategies; this could ultimately have a substantial impact on the fate of patients with Chondrosarcoma.