AGENTS FOR IN VITRO CONTROL OF ADULT STEM CELLS

描述（由申请人提供）：来自骨髓基质的间充质干细胞是多能的，并且可以离体扩增，同时保留其多潜能性。因此，它们为间充质干细胞分化的研究提供了方便的离体模型。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，从而可以在实验可获得的模型中详细研究成骨组织修复。该研究计划描述了一项旨在发现和评估逆转Dkk-1效应从而激活经典Wnt信号通路的化合物的研究。因此，这将增加MSC的成骨分化速率。该提案测试了中心假设，即小分子可能在骨退行性疾病如多发性骨髓瘤和骨生成障碍中具有通过MSC改善成骨组织修复的效用。这些分子可能有助于开发一种新的药物活性剂家族，以改善人类的自然愈合过程。有三个具体目标： 1研究经典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优化多发性骨髓瘤的小鼠模型，表现出溶骨性病变，并测试已知的GSKSb抑制剂在减少溶骨性病变形成中的效用。 3在小鼠成骨缺损模型中，测试在促进成骨组织修复中的效用。 成体干细胞有潜力在未来大大改善再生医学。这项提议旨在发现提高成人干细胞修复骨组织的内在能力的分子。这些分子在临床上与诸如成骨不全（脆骨病）和恶性骨疾病以及临界尺寸骨损伤的疾病的治疗相关。

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.