Osteoblasts and their mesenchymal progenitors in myeloma

描述（由申请人提供）：骨髓瘤治疗的重大进展导致了很高的完全缓解率;然而，所有患者最终都会复发并死于该疾病。 骨髓微环境，特别是参与骨形成和破坏的细胞，作为骨髓瘤生长和肿瘤表现的调节剂密切参与疾病过程。 我们研究的总体目标是开发一种新的骨髓瘤治疗模式，从而控制骨病有助于控制骨髓瘤的发展和进展。 为了实现这一目标，我们提出了实验来阐明成骨细胞，骨形成的骨髓细胞，在疾病过程中的作用，并制定方法来控制骨髓瘤通过控制相关的溶骨性疾病。 我们的实验将解决两个具体的目标，在体外和体内研究骨髓瘤细胞和成骨细胞之间的相互作用的后果，在生理和分子水平。 我们将在SCID-hu模型中检查体内成骨细胞数量和活性的增加是否会导致骨形成并影响骨髓瘤生长（具体目标1）。 这些实验证实了我们的假设，即增加成骨细胞的数量和活性将增加骨形成，并将控制骨髓瘤细胞的生长和存活。 我们将尝试通过单独或联合注射成骨祖细胞和甲状旁腺激素来增加成骨细胞的数量和活性。 我们还将在体外阐明骨髓瘤细胞和骨髓来源的MSC之间的相互作用对成骨细胞分化和存活以及骨髓瘤细胞存活的性质和后果（具体目标2）。 这些实验旨在追求我们的假设，即在溶骨性疾病患者中，骨髓瘤细胞破坏了间充质干细胞向成骨细胞的分化过程，并且由此产生的成骨细胞的消除促进了骨髓瘤细胞存活和疾病进展。 初步结果表明，细胞间相互作用的影响将是异质性的，我们提出的实验来研究这种多样性的潜在来源。 我们将采用最先进的蛋白质组学技术，进一步研究这些相互作用的分子水平。 我们新开发的骨髓瘤细胞/成骨细胞相互作用和骨髓瘤疾病进展的体内和体外模型，结合先进的蛋白质组学技术，是破译骨髓瘤生物学关键方面的强大工具，确定有效治疗干预的靶点，并开发用于评估治疗效果的分子工具。 拟议研究的结果将引导我们进入下一阶段，我们将设计旨在改善骨髓瘤相关骨病的治疗方案，并测试预防骨髓瘤复发和疾病进展的治疗效果。

DESCRIPTION (provided by applicant): Significant advances in the treatment of myeloma have resulted in a high rate of complete remissions; however, all patients eventually relapse and succumb to the disease. The bone marrow microenvironment, particularly the cells involved in bone formation and destruction, are intimately involved in the disease process as regulators of myeloma growth and tumor manifestations. The overall goal of our research is to develop a new paradigm of myeloma therapy, whereby control of bone disease helps to control myeloma development and progression. Working toward this goal, we propose experiments to elucidate the role of osteoblasts, the bone-forming marrow cells, in the disease process and to develop approaches to control myeloma by controlling the associated lytic bone disease. Our experiments will address two specific aims to investigate in vitro and in vivo the consequences of interactions between myeloma cells and osteoblasts, at both the physiological and molecular levels. We will examine in vivo in the SCID-hu model whether increasing the number and activity of osteoblasts results in bone formation and impacts myeloma growth (Specific Aim 1). These experiments address our hypothesis that increasing osteoblast numbers and activity will increase bone formation and will control growth and survival of myeloma cells. We will attempt to increase osteoblast number and activity by injecting osteoblast progenitor cells and parathyroid hormone, individually and in combination. We will also elucidate in vitro the nature and consequences of interactions between myeloma cells and bone marrow-derived MSC on osteoblast differentiation and survival and on myeloma cell survival (Specific Aim 2). These experiments are designed to pursue our hypothesis that, in patients with lytic bone disease, myeloma cells disrupt the mesenchymal stem cell to osteoblast differentiation process, and the resultant elimination of osteoblasts facilitates myeloma cell survival and disease progression. Preliminary results suggest that the effects of intercellular interactions will be heterogeneous, and we propose experiments to examine potential sources for this variety. We will employ state-of-the-art proteomics technologies to further investigate these interactions at the molecular level. Our newly developed in vivo and in vitro models of myeloma cell/osteoblast interactions and myeloma disease progression, combined with advanced proteomics technologies, are powerful tools for deciphering critical aspects of myeloma biology, identifying targets for effective therapeutic interventions, and developing molecular tools for evaluating treatment efficacy. The results of the proposed study will lead us to the next stage in which we will design treatment protocols aimed at improving myeloma-related bone disease and test treatment efficacy in preventing myeloma relapses and disease progression.