NF-kappaB in myeloma cell growth and survival in vivo

NF-κB 在体内骨髓瘤细胞生长和存活中的作用

• 批准号: 6897173
• 负责人: BABATUNDE OLUKAYODE OYAJOBI
• 金额: $ 15.85万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-26 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6897173
• 关键词: X ray; biological signal transduction; cell growth regulation; cell proliferation; disease /disorder onset; enzyme linked immunosorbent assay; gene expression; gene induction /repression; gene mutation; genetic promoter element; genetically modified animals; histology; laboratory mouse; multiple myeloma; neoplasm /cancer genetics; neoplasm /cancer remission /regression; neoplastic cell; neoplastic process; nuclear factor kappa beta; paraplegia; polyadenylate; transfection

DESCRIPTION (provided by applicant): Multiple myeloma (MM), a cancer that affects African-Americans disproportionately, is characterized by progressive and unremitting bone destruction. MM continues to be associated with high morbidity and mortality rates with no significant improvement in prognosis post-diagnosis in the last thirty years. The long-term goal of this proposal is for the Principal Investigator, Babatunde O. Oyajobi, PhD, to develop an independent career focused on developing novel therapeutic strategies to improve outcome in MM. In this Mentored Career Development Award application, the candidate outlines a plan that will enable him achieve this objective. Dr Oyajobi will use the KO1 to acquire additional skills in molecular biology and transgenic research and the co-sponsors, Drs Mundy and Hasty will provide an excellent training experience for the candidate in the 'state of the art' institutional facilities at UTHSC at San Antonio, TX. During year 1, the candidate will benefit from the co-mentorship of Dr Mundy, a renowned expert on effects of tumors on the skeleton, and of Dr Hasty, an expert mouse geneticist. During this period Dr Mundy will advise on biological experiments in mouse models of myeloma and Dr Hasty will provide training in specialized techniques in mouse genetics. By year 2, the candidate will be a fully independent investigator. Our hypothesis is that NF- kB activation is important for growth and survival of myeloma cells and tumor progression in vivo. The impetus for the proposal is the finding that expression in myeloma cells, of a dominant-negative (deltaF) mutant of the E3 Ubiquitin ligase betaTrCP/FWD1 that regulates NF-kB signaling, significantly reduced tumor growth in mice in vivo. The proposed studies now seek to elucidate the mechanisms mediating the effect of the transcription factor in myeloma. The Specific Aims of the proposal are: (i) To determine the contribution of the non-canonical NF-kB signaling pathway to myeloma growth/survival in vitro and in vivo (ii) To determine whether inhibition of NF-kB signaling in myeloma cells in established tumors results in tumor regression or reduced rate of tumor growth as well as prolongs survival in mice. The aims of this proposal will be addressed using a variety of approaches including transfection experiments, targeted transgenesis and in vivo (mouse) studies and other methods consistent with the proposed research career plan of the candidate. The research outlined will provide the basis for generation of novel therapeutic approaches to treat MM.

描述（由申请人提供）：多发性骨髓瘤 (MM) 是一种对非裔美国人影响尤为严重的癌症，其特征是进行性且持续的骨质破坏。 MM 仍然与高发病率和死亡率相关，并且在过去三十年中诊断后的预后没有显着改善。该提案的长期目标是首席研究员 Babatunde O. Oyajobi 博士发展独立的职业生涯，专注于开发新的治疗策略以改善 MM 的治疗结果。在这份指导职业发展奖申请中，候选人概述了一个能够帮助他实现这一目标的计划。 Oyajobi 博士将利用 KO1 获得分子生物学和转基因研究方面的额外技能，共同赞助者 Mundy 博士和 Hasty 博士将在德克萨斯州圣安东尼奥市 UHSC 的“最先进”机构设施中为候选人提供卓越的培训体验。在第一年，候选人将受益于肿瘤对骨骼影响的著名专家 Mundy 博士和小鼠遗传学专家 Hasty 博士的共同指导。在此期间，Mundy 博士将就骨髓瘤小鼠模型的生物实验提供建议，Hasty 博士将提供小鼠遗传学专业技术的培训。到第二年，候选人将成为一名完全独立的调查员。我们的假设是 NF-kB 激活对于骨髓瘤细胞的生长和存活以及体内肿瘤进展很重要。该提议的推动力是发现，调节 NF-kB 信号传导的 E3 泛素连接酶 betaTrCP/FWD1 的显性失活 (deltaF) 突变体在骨髓瘤细胞中的表达，可显着减少小鼠体内肿瘤的生长。拟议的研究现在试图阐明介导转录因子在骨髓瘤中的作用的机制。该提案的具体目标是：(i) 确定非经典 NF-kB 信号通路对体外和体内骨髓瘤生长/存活的贡献 (ii) 确定抑制已建立肿瘤的骨髓瘤细胞中的 NF-kB 信号传导是否会导致肿瘤消退或降低肿瘤生长率以及延长小鼠的生存期。该提案的目标将通过多种方法来解决，包括转染实验、靶向转基因和体内（小鼠）研究以及与候选人提出的研究职业计划一致的其他方法。概述的研究将为产生治疗多发性骨髓瘤的新治疗方法奠定基础。