NF-kappaB in myeloma cell growth and survival in vivo

描述(申请人提供)：多发性骨髓瘤(MM)，一种对非裔美国人影响不成比例的癌症，以进行性和坚持性的骨破坏为特征。多发性骨髓瘤的发病率和死亡率仍然很高，在过去的30年里，诊断后的预后没有明显的改善。这项建议的长期目标是首席研究员Babatunde O.Oyajobi博士发展一个独立的职业生涯，专注于开发新的治疗策略来改善MM的结果。在这个有指导的职业发展奖申请中，候选人概述了一个使他能够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更多技能，联合赞助商DRS Mundy和Hasty将在德克萨斯州圣安东尼奥的UTHSC的最先进的机构设施中为候选人提供出色的培训经验。在第一年，候选人将受益于芒迪博士和哈蒂斯博士的共同指导。芒迪博士是一位著名的肿瘤对骨骼影响的专家，哈蒂斯博士是一位老鼠遗传学家。在此期间，芒迪博士将为骨髓瘤小鼠模型的生物学实验提供建议，哈斯特博士将提供小鼠遗传学方面的专门技术培训。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，核因子-kB的激活对骨髓瘤细胞的生长和存活以及体内的肿瘤进展非常重要。这一提议的动机是发现在骨髓瘤细胞中，调节核因子-kB信号的E3泛素连接酶BetaTrCP/FWD1的显性-负性(DeltaF)突变体的表达显著减少了小鼠体内的肿瘤生长。拟议的研究现在试图阐明转录因子在骨髓瘤中的作用机制。该方案的具体目的是：(1)确定非规范的核因子-kB信号通路在骨髓瘤生长/存活中的作用；(2)确定在已建立的肿瘤中抑制骨髓瘤细胞中的核因子-kB信号是否会导致肿瘤消退或肿瘤生长速度减慢以及延长小鼠的生存时间。这项建议的目标将使用多种方法来解决，包括转基因实验、靶向转基因和体内(小鼠)研究以及与候选人提出的研究生涯规划一致的其他方法。概述的研究将为产生治疗MM的新的治疗方法提供基础。

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.