AGENTS FOR IN VITRO 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具有多能性，可以在体外扩增同时保持其多能性。因此，它们为间充质干细胞分化的研究提供了一个方便的离体模型。更具体地说，干细胞增殖与成骨细胞分化的过程可以被密切监测，从而可以在实验模型中详细研究成骨组织修复。本研究计划描述了一项研究，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。因此，这将增加MSCs的成骨分化率。这一建议验证了一个中心假设，即小分子可能在改善骨退行性疾病（如多发性骨髓瘤和成骨不全）中MSCs的成骨组织修复中发挥作用。这些分子可能有助于开发一种新的药物活性药物家族，以改善人类的自然愈合过程。有3个具体目标：

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.