INTRINSIC AND INDUCED GROWTH CONTROL IN SCID HU MYELOMA MODEL

描述：（申请人的描述）多发性骨髓瘤仍然是一种无法治愈的疾病。 尽管在提高发病率方面取得了相当大的进展， 患者完全缓解。复发是由骨髓瘤引起的 具有自我更新能力的细胞。这些细胞甚至可以存活， 最积极的治疗。骨髓瘤细胞与其 微环境通过粘附分子和细胞因子提供骨髓瘤 细胞与避难所，保护细胞免受自发和药物诱导 凋亡这个项目的长期目标是阐明 骨髓瘤在分子和细胞水平作为指导，以更好的临床 疾病的管理。该项目所涉及的中心假设是： 骨髓瘤和间质相互作用导致支持性微环境， 使骨髓瘤浆细胞达到取之不尽的状态， 繁殖和疾病生存，并最终发展抵抗力， 药物治疗通过直接靶向骨髓瘤浆细胞， 干扰支持性和保护性微环境的元素， 我们就能开发出有效的骨髓瘤治疗方法。我们的具体目标是： (1)通过改变骨髓瘤细胞的形态， 骨髓环境我们将确定正常骨髓基质 可以支持骨髓瘤细胞的持续增殖。我们将确定 骨髓瘤细胞生长所需的支持性微环境元素 通过破坏破骨细胞和血管内皮细胞的功能 并确定对骨髓瘤细胞存活和生长的影响 和细胞因子环境。这些研究将揭示以下方面的重要性： 破骨细胞和血管内皮细胞，支持骨髓瘤。(2)到 防止骨髓瘤出现耐药性。我们将确定 骨髓基质环境促进耐药性的出现， 研究体内耐药性的分子机制是否是 与体外耐药性的报告相同。这些研究将使 光在体内耐药性的发展，并将指出， 提高治疗效果的策略。(3)确定的作用 骨髓瘤患者血液和骨髓中的前浆细胞 维持疾病进程。我们将确定净化的能力 骨髓瘤浆细胞达到无限增殖的状态， 在SCID-hu宿主中骨髓瘤表现的产生，以及前浆细胞是否 患者骨髓和血液中的细胞能够 需要在SCID-hu宿主中产生持续的症状性骨髓瘤。这些 研究结果将确定治疗是否需要考虑前浆细胞细胞， 骨髓瘤疾病过程的重要组成部分。根据其结论， 本项目下的工作将确定所报告的 骨髓瘤骨髓微环境的异常与疾病过程， 阐明了破骨细胞和血管内皮细胞在 支持骨髓瘤细胞，确定是否破坏破骨细胞功能 并且干扰新血管生成抑制骨髓瘤细胞的生长， 提高治疗效果，证明了骨髓瘤的能力 浆细胞维持疾病过程，并确定是否为浆细胞前期 克隆细胞具有持续的积极作用， 疾病过程。

DESCRIPTION: (Applicant's Description) Multiple myeloma remains an incurable disease, in spite of the considerable progress made in increasing the rate of complete remissions achieved by patients. Relapses are caused by the myeloma cells with self-renewal capacity. These cells are able to survive even the most aggressive treatment. Interactions of the myeloma cells with their microenvironment through adhesion molecules and cytokines provides the myeloma cells with a sanctuary, protecting the cells from spontaneous and drug-induced apoptosis. The long-term goals of this project are to elucidate the biology of myeloma at the molecular and cellular level as a guide to better clinical management of the disease. The central hypothesis this project addresses is: Myeloma and stroma interactions result in a supportive microenvironment that allows the myeloma plasma cells to achieve a state of inexhaustible proliferation and disease subsistence, and to eventually develop resistance to drug therapy. By targeting the myeloma plasma cells directly and by interfering with elements of the supportive and protective micro-environment, we can develop effective therapies against myeloma. Our specific aims are: (1) To control the growth of myeloma and its manifestations by changing the bone marrow environment. We will determine whether normal bone marrow stroma can support sustained proliferation of myeloma cells. We will identify elements of the supportive micro-environment required for myeloma cell growth by disrupting the functions of the osteoclasts and vascular endothelial cells and determine the effects on the survival and the growth of the myeloma cells and on the cytokine milieu. These studies will reveal the importance of osteoclasts and vascular endothelial cells, in supporting myeloma. (2) To prevent emergence of drug resistance in myeloma. We will determine if the bone marrow stromal environment facilitates emergence of drug resistance, and investigate if the molecular mechanisms of in vivo drug resistance are the same as have been reported for in vitro resistance. These studies will shed light on the development of drug resistance in vivo, and will point to strategies that will increase treatment efficacy. (3) To determine the role of pre-plasmacytic cells in the blood and bone marrow of myeloma patients in sustaining the disease process. We will determine the ability of purified myeloma plasma cells to achieve a state of inexhaustible proliferation and production of myeloma manifestations in the SCID-hu host, and whether the preplasmacytic cells in the bone marrow and blood of patients are able and required to produce sustained symptomatic myeloma in the SCID-hu host. These findings will determine if therapy needs to consider preplasmacytic cells as an important component of the myeloma disease process. By its conclusion, work under this project will have determined the significance of reported anomalies in the myeloma bone marrow microenvironment to the disease process, elucidated the role of osteoclasts and vascular endothelial cells in supporting myeloma cells, determined whether disrupting osteoclast function and interfering with neo-angiogenesis inhibits growth of myeloma cells and increases the efficacy of treatment, demonstrated the ability of myeloma plasma cells to maintain the disease process, and determined whether preplasmacytic clonal cells have a continuous active role in sustaining the disease process.