NF-kappaB in myeloma cell growth and survival in vivo

描述（由申请人提供）：多发性骨髓瘤（MM）是一种不成比例地影响非洲裔美国人的癌症，其特征是进行性和持续的骨破坏。MM仍然与高发病率和死亡率相关，在过去的三十年中，诊断后的预后没有显著改善。该提案的长期目标是主要研究者Babatunde O。Oyajobi博士将发展独立的职业生涯，专注于开发新型治疗策略以改善MM的结果。在这份指导职业发展奖申请中，候选人概述了一项使他能够实现这一目标的计划。Oyajobi博士将利用KO 1获得分子生物学和转基因研究方面的额外技能，共同赞助商Mundy博士和Hasty博士将在德克萨斯州圣安东尼奥的UTHSC“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Mundy博士和Hasty博士的共同指导，Mundy博士是肿瘤对骨骼影响的著名专家，Hasty博士是小鼠遗传学专家。在此期间，Mundy博士将为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-κ B的激活对于骨髓瘤细胞的生长和存活以及体内肿瘤的进展是重要的。该提议的动力是发现在骨髓瘤细胞中表达调节NF-kB信号传导的E3泛素连接酶β TrCP/FWD 1的显性阴性（deltaF）突变体，显着降低小鼠体内肿瘤生长。现在提出的研究试图阐明介导骨髓瘤中转录因子作用的机制。该提案的具体目的是：（i）确定非经典NF-kB信号传导途径对体外和体内骨髓瘤生长/存活的贡献（ii）确定在已建立的肿瘤中抑制骨髓瘤细胞中的NF-kB信号传导是否导致肿瘤消退或肿瘤生长速率降低以及小鼠的骨髓瘤存活。该提案的目的将使用各种方法来解决，包括转染实验，靶向转基因和体内（小鼠）研究以及与候选人拟议的研究职业计划一致的其他方法。概述的研究将为治疗MM的新治疗方法的产生提供基础。

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.