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

描述（由申请人提供）：Raquel Sitcheran博士正在北卡罗来纳州大学Albert Baldwin博士的实验室进行博士后工作，其长期职业目标是成为学术环境中的独立科学家。Sitcheran博士的研究旨在阐明转录因子NF-κ B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NF-κ B可以通过抗凋亡机制促进细胞存活，因此靶向抑制NF-κ B活性的抗癌药物可以提高化疗治疗的疗效。然而，NF-κ B也可以通过抑制细胞存活途径促进细胞死亡。类似地，N-myc癌基因在侵袭性神经母细胞瘤中频繁扩增，既可以促进细胞存活，也可以拮抗细胞存活。因此，有效的癌症疗法不能简单地通过靶向抑制NF-κ B或N-mvc来实现。理解NF-κ B和N-myc如何被不同的信号调节以指定靶基因的激活或抑制，从而促进选择性靶向NF-κ B和/或N-mvc功能的抗癌药物的设计是极其重要的。 初步数据表明：1）NF-κ B和N-myc在体内可以相互作用; 2）N-myc可以抑制NF-κ B的活性。考虑到NF-κ B和N-myc在调节细胞存活和肿瘤发生中的重要作用，有时是相反的作用，Sitcheran博士的直接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NF-κ B和N-myc之间相互作用的生物学意义以及N-myc抑制NF-κ B的机制。该提案将阐明NF-κ B如何响应于不同的发育，生理和病理信号，以指定独特的基因表达模式。将研究以下特定目的：1）表征NF-KB：N-myc蛋白复合物; 2）研究N-myc调节NF-KB活性的机制; 3）鉴定和表征由N-myc和NF-KB两者调节的基因;和4）分析N-myc和NF-KB在神经母细胞瘤发病机制中的协同性。这些研究有可能为靶向NF-κ B和N-myc调控的致癌通路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.