INTRINSIC AND INDUCED GROWTH CONTROL IN SCID HU MYELOMA MODEL

SCID HU 骨髓瘤模型中的内在和诱导生长控制

• 批准号: 6594584
• 负责人: JOSHUA EPSTEIN
• 金额: $ 27.95万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-01 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6594584
• 关键词: SCID mouse; angiogenesis inhibitors; bone marrow; cell growth regulation; cell proliferation; cellular oncology; disease /disorder model; drug resistance; molecular oncology; multiple myeloma; neoplasm /cancer chemotherapy; neoplastic cell; neoplastic growth; osteoclasts; pathologic process; plasma cells; vascular endothelium

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.

描述：(申请者描述)多发性骨髓瘤仍然是无法治愈的 疾病，尽管在提高死亡率方面取得了相当大的进展 患者的完全缓解。复发是由骨髓瘤引起的 具有自我更新能力的细胞。这些细胞能够存活，即使是 最具侵略性的治疗。骨髓瘤细胞与其自身的相互作用 通过黏附分子和细胞因子的微环境提供骨髓瘤 具有避难所的细胞，保护细胞免受自发和药物诱导 细胞凋亡。这个项目的长期目标是阐明生物学 在分子和细胞水平上对骨髓瘤的研究，以指导更好的临床 疾病的管理。这个项目的中心假设是： 骨髓瘤和间质的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用之不竭的状态 扩散和疾病生存，并最终形成对 药物治疗。通过直接靶向骨髓瘤浆细胞和通过 干扰支持和保护微环境的要素， 我们可以开发出针对骨髓瘤的有效疗法。我们的具体目标是： (1)控制骨髓瘤的生长及其表现，通过改变 骨髓环境。我们将确定正常的骨髓基质是否 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要素 通过破坏破骨细胞和血管内皮细胞的功能 并测定对骨髓瘤细胞存活和生长的影响 对细胞因子环境的影响。这些研究将揭示 破骨细胞和血管内皮细胞，支持骨髓瘤。(2)至 防止骨髓瘤出现耐药性。我们将确定是否 骨髓基质环境促进耐药的产生 研究体内耐药的分子机制是否与 与已报道的体外耐药性相同。这些研究将使 关于体内耐药的发展，并将指出 将提高治疗效果的策略。(三)确定党的作用 北京地区骨髓瘤患者外周血和骨髓中浆前细胞的检测 维持疾病的进程。我们将测定纯化的能力 骨髓瘤浆细胞达到取之不尽的增殖状态 在SCID-HU宿主中产生骨髓瘤的表现，以及前浆细胞性 患者骨髓和血液中的细胞能够 在SCID-HU宿主中产生持续症状性骨髓瘤所需的。这些 研究结果将决定治疗是否需要将前浆细胞视为 骨髓瘤疾病过程中的一个重要组成部分。根据它的结论， 该项目下的工作将确定所报告的 骨髓瘤骨髓微环境异常对疾病进程的影响， 阐明破骨细胞和血管内皮细胞在骨损伤中的作用 支持骨髓瘤细胞，确定是否破坏破骨细胞功能 干扰新生血管生成抑制骨髓瘤细胞的生长和 提高疗效，彰显治疗骨髓瘤的能力 维持疾病进程的浆细胞，并确定是否有浆细胞前 克隆细胞具有持续活跃的作用，以维持 疾病过程。