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

DKK-1，有助于骨肉瘤骨病变的形成

• 批准号: 7720779
• 负责人: CARL A. GREGORY
• 金额: $ 21.28万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7720779
• 关键词: Adipose tissue; Antibodies; Blood; Bone Diseases; Bone Marrow; Computer Retrieval of Information on Scientific Projects Database; Disease; Funding; Glycogen (Starch) Synthase; Grant; Human; Institution; Lesion; Ligands; Malignant - descriptor; Malignant Neoplasms; Mediating; Mesenchymal Stem Cells; Modeling; Multiple Myeloma; Mus; Osteoblasts; Osteogenesis; PPAR gamma; Patients; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Phosphotransferases; Process; Proteins; Research; Research Personnel; Resources; Rodent; Signal Pathway; Signal Transduction; Skeleton; Source; Testing; Tissues; United States National Institutes of Health; osteosarcoma; progenitor

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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 该提案测试了一个中心假设，即骨抑制蛋白配体 Dkk-1 的表达通过抑制间充质干细胞成骨分化的自然过程，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来药理学诱导经典 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，因此可能逆转某些骨骼恶性疾病造成的损伤。有4个具体目标。 + A1。 “为了进一步验证 Dkk-1 作为人类恶性和退行性骨疾病的血液/组织标记物的效用。 + A2。 “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经典 Wnt 信号传导与 PPAR gamma 介导的信号传导途径之间的离体串扰。 + A3。 “目的是检查化合物、蛋白质和抗体对啮齿动物血液和骨髓中脂肪和成骨细胞祖细胞水平的影响，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。 “利用来自骨肉瘤和多发性骨髓瘤患者的已建立的癌细胞系和组织，检查此类药物在恶性骨病小鼠模型中的潜在骨诱导作用。