NF-kappaB N-myc in Oncogenic Pathways of the CNS

描述(申请人提供)：拉克尔·西切兰博士在北卡罗来纳大学阿尔伯特·鲍德温博士的实验室从事博士后工作，长期职业目标是在学术环境中成为一名独立科学家。Sitcheran博士的研究旨在阐明转录因子NF-KB如何响应不同的细胞外信号来控制基本过程，如细胞增殖、凋亡和恶性转化。由于核因子-kB可以通过抗细胞凋亡机制促进细胞存活，靶向抑制核因子-kB活性的抗癌药物可以提高化疗的疗效。然而，核因子-KB也可以通过抑制细胞生存途径来促进细胞死亡。同样，N-myc癌基因在侵袭性神经母细胞瘤中经常被扩增，既可以促进细胞存活，也可以拮抗细胞存活。因此，有效的癌症治疗不能简单地通过靶向抑制NF-KB或N-MVC来实现。了解不同的信号是如何调控NF-KB和N-myc的，从而确定靶基因的激活或抑制，从而促进针对NF-KB和/或N-MVC功能的抗癌药物的设计是至关重要的。 初步研究表明：1)N-myc与核因子-kB在体内存在相互作用；2)N-myc可抑制核因子-kB的活性。鉴于核因子-kB和N-myc在调节细胞存活和肿瘤发生中扮演的重要角色，有时甚至是对立的角色，Sitcheran博士的近期目标是获得使用蛋白质组学、微阵列和小鼠模型系统的额外培训，以评估核因子-kB和N-myc之间相互作用的生物学意义以及nmyc抑制核因子-kB的机制。这项建议将阐明核因子-KB如何对不同的发育、生理和病理信号做出反应，以确定独特的基因表达模式。本研究的主要目的包括：1)鉴定N-myc蛋白复合体；2)研究N-myc调控核因子-kB活性的机制；3)鉴定和鉴定N-myc和核因子-kB共同调控的基因；4)分析N-myc和核因子-kB在神经母细胞瘤发病机制中的协同作用。这些研究有可能为针对由核因子-kB和N-myc调控的致癌途径的药物设计提供新的见解。

DESCRIPTION (provided by applicant): Dr. Raquel Sitcheran is conducting postdoctoral work in the laboratory of Dr. Albert Baldwin at the University of North Carolina, with the long-term career goal of becoming an independent scientist in an academic environment. Dr. Sitcheran's research is directed at elucidating how the transcription factor NF-KB responds to diverse extracellular signals to control fundamental processes, such as cell proliferation, apoptosis and malignant transformation. Because NF-KB can promote cell survival through anti-apoototic mechanisms, anti-cancer drugs targeting inhibition NF-KB activity can improve the efficacy of chemotherapy treatments. However, NF-KB can also promote cell death by repressing cell survival pathways. Similarly, the N-myc oncogene, which is frequently amplified in aggressive neuroblastoma, can both promote and antagonize cell survival. Therefore, efficacious cancer therapies cannot be achieved simply by targeting inhibition of NF-KB or N-mvc. It is of utmost importance to understand how NF-KB and N-myc are regulated by diverse signals to specify activation or repression of target genes, thereby facilitating the design of anticancer drugs that selectively target NF-KB and/or N-mvc functions. Preliminary data suggest that 1) NF-KB and N-myc can interact in vivo and 2) N-myc can repress the activity of NF-KB. Given the important, and sometimes opposing, roles that NF-KB and N-myc play in regulating cell survival and oncogenesis, Dr. Sitcheran's immediate goals are to gain additional training in the use of proteomics, microarray and mouse model systems to evaluate the biological significance of the interaction between NF-KB and N-myc and the mechanism by which Nmyc represses NF-KB. This proposal will elucidate how NF-KB responds to diverse developmental, physiological and pathological signals to specify unique patterns of gene expression. The following Specific Aims will be investigated: 1) Characterization of the NF-KB:N-myc protein complex; 2) Investigation of the mechanism by which N-myc regulates NF-KB activity 3) Identification and characterization of genes regulated by both N-myc and NF-KB; and 4)Analysis of cooperativity between N-myc and NF-KB in neuroblastoma pathogenesis. These studies have the potential to offer new insight into drug design targeting oncogenic pathways regulated by NF-KB and N-myc.