Agents for in vivo control of adult stem cells

描述(申请人提供)：来自骨髓基质的间充质干细胞是多能的，可以在体外扩增，同时保持其多潜能。为间充质干细胞分化的研究提供了一种方便的体外模型。更具体地说，可以密切监测干细胞增殖与成骨细胞分化的过程，从而允许在实验上可访问的模型中对成骨组织修复进行详细研究。这项研究计划描述了一项旨在发现和评估逆转DKK-1作用的化合物，从而激活典型的Wnt信号通路的调查。因此，这将增加MSCs的成骨分化速度。这一建议验证了中心假设，即小分子可能在多发性骨髓瘤和成骨不全等骨骼退行性疾病中通过骨髓间充质干细胞改善成骨组织修复方面具有实用价值。这些分子可能有助于开发一类新的药物活性物质，以改善人类的自然愈合过程。具体目标有三个： 1研究经典的Wnt抑制剂Dickkopf-1和糖原合成酶-激酶-3-β(GSKSb)抑制剂对骨髓间充质干细胞体外成骨分化的影响。 2优化表现溶骨性病变的多发性骨髓瘤小鼠模型，并测试已知的GSKSb抑制剂在减少溶骨性病变形成方面的效用。 3在成骨不全小鼠模型上测试其对促进成骨组织修复的作用。 成人干细胞有可能极大地改善未来的再生医学。这项提议旨在发现能够提高成人干细胞修复骨组织固有能力的分子。这些分子在临床上与治疗成骨不全(脆性骨病)、恶性骨病和临界大小骨损伤等疾病有关。

DESCRIPTION (provided by applicant): Mesenchymal stem cells from bone marrow stroma are pluripotent and can be expanded ex vivo whilst retaining their multi-potentiality. They therefore provide a convenient ex vivo model for the study of mesenchymal stem cell differentiation. More specifically, the process of stem cell proliferation coupled to osteoblastic differentiation can be closely monitored, permitting the detailed investigation of osteogenic tissue repair in an experimentally accessible model. This research plan describes an investigation designed to discover and evaluate compounds that reverse the effect of Dkk-1 thereby activating the canonical Wnt signaling pathway. This would therefore increase the rate of osteogenic differentiation by MSCs. This proposal tests the central hypothesis that small molecules may have utility in improving osteogenic tissue repair by MSCs in bone degenerative diseases such as multiple myeloma and osteogenesis imperfecta. These molecules could contribute to the development of a novel family of pharmaceutically active agents for the improvement of the natural healing process in humans. There are 3 Specific Aims: 1 To investigate the effect of the canonical Wnt inhibitor dickkopf-1 and glycogen-synthase-kinase-3-beta (GSKSb) inhibitors on osteogenic differentiation by mesenchymal stem cells in vitro. 2 To optimize a murine model of multiple myeloma that exhibit osteolytic lesions and to test known GSKSb inhibitors for utility in reducing the formation of osteolytic lesions. 3 To test the utility of in enhancing osteogenic tissue repair in a murine model of osteogenesis imperfecta. Adult stem cells have the potential to dramatically improve regenerative medicine in the future. This proposal is designed to discover molecules that improve the inherent capacity of adult human stem cells to repair bone tissue. These molecules are clinically relevant for the treatment of diseases such as Osteogenesis Imperfecta (brittle bone disease) and malignant bone disease and critical size bone injuries.