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: 7052084
• 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/7052084
• 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），一种影响非裔美国人不成比例的癌症，其特征是进行性骨骼和不懈的骨骼破坏。 MM继续与高发病率和死亡率相关，在过去三十年中，诊断后预后没有显着改善。该提案的长期目标是针对首席研究员Babatunde O. Oyajobi博士，旨在发展独立的职业，专注于制定新型的治疗策略以改善MM的结果。在这个指导的职业发展奖应用程序中，候选人概述了一项计划，该计划将使他实现这一目标。 Oyajobi博士将使用KO1获得分子生物学和转基因研究的额外技能，共同赞助商Mundy博士和Hasty博士将为位于德克萨斯州圣安东尼奥市UTHSC的“最先进”机构设施的候选人提供出色的培训经验。在第1年，候选人将受益于蒙迪博士的冠军专家Mundy博士，以及骨骼对骨骼影响的专家，以及小鼠遗传学家Hasty博士。在此期间，蒙迪博士将在骨髓瘤小鼠模型中就生物学实验提供建议，Hasty博士将提供小鼠遗传学专业技术的培训。到第二年，候选人将成为一个完全独立的研究员。我们的假设是NF-KB激活对于骨髓瘤细胞的生长和存活和体内肿瘤进展至关重要。该提案的动力是发现，E3泛素连接酶BetatRCP/FWD1在骨髓瘤细胞中的表达（骨髓瘤细胞）的表达显着降低了VIVO中小鼠的肿瘤生长。现在，提出的研究旨在阐明介导转录因子对骨髓瘤作用的机制。该提案的具体目的是：（i）确定非典型的NF-KB信号传导途径对骨髓瘤生长/体外的骨髓瘤生长/生存的贡献，并确定体内（II）（II）确定肿瘤肿瘤中骨髓瘤细胞中NF-KB信号的抑制是在肿瘤回归肿瘤中的骨髓瘤细胞中的抑制作用，以及肿瘤生长的生长速度以及繁殖率的生长。该提案的目的将使用多种方法来解决，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。概述的研究将为治疗MM的新型治疗方法提供基础。