DKK-1,CONTRIBUTES TO THE FORMATION OF BONE LESIONS IN OSTEOSARCOMA

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。 该提案测试了中心假设，即骨生成蛋白配体Dkk-1的表达通过抑制间充质干细胞的成骨分化的自然过程而有助于骨肉瘤和一些转移性骨疾病中骨病变的形成。通过抑制糖原合成酶激酶和抑制过氧化物酶体增殖物激活受体，药物诱导经典Wnt信号传导，加速间充质干细胞的成骨分化。这些分子阻断Dkk-1的作用，因此可能逆转某些恶性骨骼疾病造成的损害。有四个具体目标。 + A1.“进一步验证Dkk-1作为人类恶性和退行性骨病血液/组织标志物的实用性。 + A2.“为了研究在存在和不存在Dkk-1的情况下，来自骨髓基质的人类和啮齿动物间充质干细胞中典型Wnt信号传导和PPAR γ介导的信号传导途径之间的体外串扰。 + A3.“研究化合物、蛋白质和抗体对啮齿动物血液和骨髓中脂肪和成骨祖细胞水平的影响，这些化合物、蛋白质和抗体有可能调节经典Wnt和PPAR介导的信号传导。 + A4.“利用骨肉瘤和多发性骨髓瘤患者的已建立的癌细胞系和组织，在恶性骨疾病的小鼠模型中检查此类药物的潜在骨诱导作用。

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. This proposal tests the central hypothesis that expression of the osteoinhibtory protein ligand, Dkk-1,contributes to the formation of bone lesions in osteosarcoma and some metastatic bone diseases by inhibiting the natural process of osteogenic differentiation by mesenchymal stem cells. Pharmalogocal induction of canonical Wnt signaling by inhibition of glycogen synthetase kinase ¿, and inhibition of peroxisome-proliferator activated receptor ¿, accelerates osteogenic differentiation by mesenchymal stem cells. These molecules block the action of Dkk-1 and thus may reverse the damage caused by some malignant diseases of the skeleton. There are 4 specific aims. + A1. "To further validate the utility of Dkk-1 as a blood/tissue marker for malignant and degenerative bone disease in humans. + A2. "To investigate ex vivo crosstalk between canonical Wnt signaling and the PPAR gamma mediated signaling pathway in human and rodent mesenchymal stem cells from bone marrow stroma in the presence and absence of Dkk-1. + A3. "To examine the effects of compounds, proteins, and antibodies that have potential to modulate canonical Wnt and PPAR¿ mediated signaling on the levels of adipose and osteoblast progenitors in rodent blood and bone marrow. + A4. "To examine the potential osteo-inductive effect of such drugs in murine models of malignant bone disease utilizing established cancer lines and tissue derived from osteosarcoma and multiple myeloma patients.