RI COBRE: MECHANISMS OF ANGIOGENESIS IN CHONDROSARCOMA

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 软骨肉瘤是一种预后不佳的原发骨肿瘤，大多数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耐药性，因此存活率并未提高。抗血管生成治疗是一种相对较新的治疗策略，但尚未尝试用于软骨肉瘤。我们的长期目标是为将这种疗法应用于临床奠定基础。 通过识别适当的分子靶标进行练习。诱导血管生长的信号来源于对缺氧的正常生理反应，主要受缺氧诱导因子-1(HIF-1)的调节，以及肿瘤细胞中的遗传异常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，在软骨肉瘤中，由组蛋白脱乙酰酶4(HDAC4)、矮小相关转录因子2(Runx2)和血管内皮生长因子(VEGF)组成的调控生长板中软骨细胞成熟和软骨内成骨的途径被重新激活，并导致血管生成。我们的假设是基于初步数据，即软骨肉瘤细胞中HDAC4的缺失导致Runx2和VEGF表达增加。此外，还发现了转录因子Runx2的一个新靶点：受Runx2下调的p16。P16蛋白抑制血管内皮生长因子的表达，而Runx2上调血管内皮生长因子的表达。因此，Runx2表达的增加直接或间接地通过降低p16来增加血管内皮细胞生长因子。建议的实验利用一种综合的分子方法来研究HDAC4、Runx2、p16和HIF-1相互作用最终驱动软骨肉瘤血管生成的机制。 具体目的：(1)明确HDAC4和Runx2在软骨肉瘤血管内皮生长因子表达调控中的作用，评价HDAC4/Runx2正常表达对血管生成的生物学影响。(2)研究HIF-1和Runx2调控血管内皮生长因子之间的相互作用。 (3)分析Runx2下调p16表达的机制及其对血管生成的影响。了解血管生成的机制是制定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 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.