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: 7936520
• 负责人: BABATUNDE OLUKAYODE OYAJOBI
• 金额: $ 5万
• 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 2010-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7936520
• 关键词: 26S proteasome; Address; Affect; African American; Arts; Biological; Cell Death; Cells; Data; Development; Diagnosis; Disease remission; Doctor of Philosophy; Dominant-Negative Mutation; Employee Strikes; Gene Transfer Techniques; Generations; Genetic; Goals; Growth; Homologous Gene; Impairment; In Vitro; K-Series Research Career Programs; Lymphoid Cell; Malignant Neoplasms; Mediating; Mentors; Mentorship; Methods; Molecular Biology; Morbidity - disease rate; Multiple Myeloma; Mus; Mutate; NF-kappa B; NFKB Signaling Pathway; Outcome; Patients; Peptides; Pharmaceutical Preparations; Principal Investigator; Process; Proteasome Inhibition; Proteins; Refractory Disease; Research; Research Personnel; Role; Signal Pathway; Signal Transduction; Skeleton; System; Techniques; Training; Transfection; Transgenic Organisms; Ubiquitin; base; beta-Transducin Repeat-Containing Proteins; bone; career; cell growth; effective therapy; experience; improved; in vivo; inhibitor/antagonist; mortality; mouse model; multicatalytic endopeptidase complex; mutant; novel; novel therapeutic intervention; novel therapeutics; outcome forecast; research study; skills; transcription factor; tumor; tumor growth; tumor progression; ubiquitin-protein ligase

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）是一种严重影响非裔美国人的癌症，其特征是进行性和持续性的骨骼破坏。在过去的30年里，MM仍然与高发病率和死亡率相关，诊断后的预后没有显著改善。该提案的长期目标是让首席研究员Babatunde O. Oyajobi博士发展一项独立的职业，专注于开发新的治疗策略，以改善MM的结果。在这份指导职业发展奖申请中，候选人概述了一个能够使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，共同发起人Mundy博士和Hasty博士将在德克萨斯州圣安东尼奥市UTHSC的“最先进”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博士的共同指导，Mundy博士是一位著名的肿瘤对骨骼的影响专家，而Hasty博士是一位老鼠遗传学专家。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方面的培训。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激活对骨髓瘤细胞的生长和存活以及肿瘤在体内的进展是重要的。提出这一建议的动机是发现在骨髓瘤细胞中表达E3泛素连接酶betaTrCP/FWD1的显性阴性（deltaF）突变体，该突变体调节NF-kB信号，可显著降低小鼠体内肿瘤生长。目前提出的研究旨在阐明转录因子在骨髓瘤中的作用机制。该提案的具体目的是：(i)确定非规范NF-kB信号通路对体外和体内骨髓瘤生长/存活的贡献（ii）确定在已建立肿瘤的骨髓瘤细胞中抑制NF-kB信号是否会导致肿瘤消退或降低肿瘤生长速度，并延长小鼠的生存期。该提案的目的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）研究以及与候选人拟议的研究职业计划相一致的其他方法。概述的研究将为产生治疗MM的新治疗方法提供基础。

项目成果

Characterization and cytotoxicity of self-organized assemblies of curcumin and amphiphatic poly(ethylene glycol).

• DOI: 10.1166/jbn.2009.1025
• 发表时间: 2009-04
• 期刊: Journal of biomedical nanotechnology
• 影响因子: 2.9
• 作者: K. Sou;B. Oyajobi;B. Goins;W. Phillips;E. Tsuchida

Bone marrow-targeted liposomal carriers.

骨髓靶向脂质体载体。

• DOI: 10.1517/17425247.2011.553218
• 发表时间: 2011
• 期刊: Expert opinion on drug delivery
• 影响因子: 6.6
• 作者: Sou,Keitaro;Goins,Beth;Oyajobi,BabatundeO;Travi,BrunoL;Phillips,WilliamT
• 通讯作者: Phillips,WilliamT

Plumbagin inhibits osteoclastogenesis and reduces human breast cancer-induced osteolytic bone metastasis in mice through suppression of RANKL signaling.

• DOI: 10.1158/1535-7163.mct-11-0731
• 发表时间: 2012-02
• 期刊: Molecular cancer therapeutics
• 影响因子: 5.7
• 作者: Sung B;Oyajobi B;Aggarwal BB
• 通讯作者: Aggarwal BB

Therapeutic antitumor efficacy of anti-CD137 agonistic monoclonal antibody in mouse models of myeloma.

• DOI: 10.1158/1078-0432.ccr-08-0285
• 发表时间: 2008-11-01
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Murillo O;Arina A;Hervas-Stubbs S;Gupta A;McCluskey B;Dubrot J;Palazón A;Azpilikueta A;Ochoa MC;Alfaro C;Solano S;Pérez-Gracia JL;Oyajobi BO;Melero I
• 通讯作者: Melero I