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Osteosarcoma Translational Research

骨肉瘤转化研究

基本信息

批准号：
8507628
负责人：
QIPING ZHENG
金额：
$ 18.77万
依托单位：
RUSH UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-09 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8507628
关键词：
Adipocytes Affect Apoptosis Apoptotic Biological Biological Assay Bone Development Cancer Etiology Candidate Disease Gene Cartilage Cessation of life Characteristics Child Childhood Chondrocytes Collagen Gene Data Development Diagnosis Diagnostic Digit structure Etiology Evaluation Event Family Fibroblasts Gene Expression Genes Genetic Goals Growth Heterogeneity Histology Human Image Knockout Mice Limb structure Link Malignant Bone Neoplasm Malignant Neoplasms Mediating Modeling Molecular Molecular Diagnosis Molecular Profiling Molecular Target Monitor Mus Mutation Neoplasm Metastasis Oncogenic Osteoblasts Osteogenesis Pathogenesis Phenotype Play Principal Investigator Publishing RB1 gene Reporting Research Research Personnel Resources Role Sampling Staging Syndrome TP53 gene Testing Tissue Microarray Tissue Sample Tissues Transgenic Mice Translational Research Tumor Suppressor Proteins Tumor Tissue age group base cartilage development cell type clinically relevant in vivo long bone member molecular marker mouse model new therapeutic target novel osteoblast differentiation osteosarcoma outcome forecast overexpression promoter screening skeletal therapeutic target tool transcription factor tumor tumorigenesis young adult

项目摘要

DESCRIPTION (provided by applicant): This project aims to determine how chondrocyte maturation plays a role in osteosarcoma (OS) oncogenesis. The long term goals are to advance the diagnosis of OS and to identify novel therapeutic targets for OS treatment. OS is the most common bone cancer in children and young adults. It is also the leading cause of cancer death in this age group. The causes of OS development are unknown. Previous studies have suggested the importance of osteoblast activity in its tumorigenesis, since the characteristic feature of OS is the abnormal bone formation in its tumor tissue and the predominant cell type within OS is osteoblast. However, besides osteoblasts, other cell types such as chondrocytes, adipocytes, and fibroblasts also appear within OS. How these cell types contribute to OS pathogenesis remain poorly understood. Previously, cartilage formation has been reported both in mouse and in human OS tissues (Walkley et al., 2008). This is intriguing, since cartilage formation is an essential step of endochondral bone formation, suggesting its putative role in OS development. In this application, the investigators hypothesize that chondrocyte maturation, a critical stage of cartilage development during endochondral bone formation, plays a role in the initiation and progression of OS, possibly through a mechanism relating to chondrocyte apoptosis. To test above hypothesis, the investigators propose to delineate the correlation of chondrocyte maturation with OS development using established mouse OS models and their own novel transgenic mouse models, as well as human OS tissue samples. Recently, preliminary results and/or pending publishing data from the principal investigator's group have shown that transgenic mice overexpressing Runx2 or P63 in hypertrophic chondrocytes result in delayed or accelerate chondrocyte maturation respectively. Given the important function of Runx2 and P63 genes during bone and cancer formation, these mouse models provide unique resources to genetically determine how chondrocyte maturation affects OS progression in a p53 and pRb deficient OS mouse model (Walkley et al., 2008). Three specific aims are proposed. Aim1 is expected to show that delayed chondrocyte maturation in Col10a1-Runx2 mice will accelerate OS initiation and progression due to increased expression of anti- apoptotic marker genes. Aim2 is expected to show that accelerate chondrocyte maturation in Col10a1- TAP63? mice delays OS development, possibly through a proapoptotic mechanism. Aim 3 focuses on analysis of candidate genes (such as P53, P63, RB1, SOX9, RUNX2, etc.), relating to both OS pathogenesis and chondrocyte maturation, in human OS tissues using tissue-array, qRT-PCR and novel COLD-PCR approaches. Successful completion of these aims will advance our understanding of OS etiology and identify promoters of chondrocyte maturation as novel therapeutic targets for OS.

描述(由申请人提供)：该项目旨在确定软骨细胞成熟如何在骨肉瘤(OS)肿瘤发生中起作用。长期目标是促进OS的诊断，并为OS治疗寻找新的治疗靶点。OS是儿童和年轻人最常见的骨癌。它也是这个年龄段癌症死亡的主要原因。操作系统开发的原因尚不清楚。以往的研究表明成骨细胞活性在其肿瘤发生中的重要性，因为OS的特征是其肿瘤组织中异常的骨形成，而OS中的主要细胞类型是成骨细胞。然而，除成骨细胞外，OS内还出现其他类型的细胞，如软骨细胞、脂肪细胞和成纤维细胞。这些细胞类型如何在OS发病机制中发挥作用仍然知之甚少。此前，在小鼠和人类OS组织中都有软骨形成的报道(Walkley等人，2008年)。这是耐人寻味的，因为软骨形成是软骨内骨形成的一个重要步骤，这表明它在OS的发展中可能起到作用。在这一应用中，研究人员推测，软骨细胞成熟是软骨内骨形成过程中软骨发育的关键阶段，可能通过与软骨细胞凋亡有关的机制在OS的发生和发展中发挥作用。为了验证上述假设，研究人员建议使用已建立的小鼠OS模型和他们自己的新型转基因小鼠模型以及人类OS组织样本来描述软骨细胞成熟与OS发育的相关性。最近，主要研究小组的初步结果和/或即将发表的数据表明，在肥大的软骨细胞中过度表达Runx2或P63的转基因小鼠分别导致软骨细胞成熟延迟或加速。鉴于Runx2和p63基因在骨形成和癌症形成中的重要作用，这些小鼠模型提供了独特的资源来从遗传学上确定软骨细胞成熟如何影响P53和pRb缺陷的OS小鼠模型的OS进展(Walkley等人，2008年)。提出了三个具体目标。AIM1有望证明，COL10a1-Runx2小鼠软骨细胞的延迟成熟将通过增加抗凋亡标记基因的表达而加速OS的启动和进展。AIM2有望在COL10a1-TAp63？小鼠延缓了OS的发育，可能是通过促凋亡机制。目的利用组织芯片、定量逆转录聚合酶链式反应(qRT-PCR)和新型冷-聚合酶链式反应(COLD-PCR)技术，分析人OS组织中与OS发病和软骨细胞成熟相关的候选基因(如P53、p63、RB1、SOX9、RUNX2等)。这些目标的成功实现将促进我们对OS病因的理解，并将软骨细胞成熟的促进剂确定为OS的新治疗靶点。