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

简介（申请人提供）：Raquel Sitcheran博士在北卡罗来纳大学Albert Baldwin博士的实验室进行博士后工作，长期职业目标是在学术环境中成为一名独立的科学家。Sitcheran博士的研究方向是阐明转录因子NF-KB如何响应各种细胞外信号来控制基本过程，如细胞增殖、细胞凋亡和恶性转化。由于NF-KB可以通过抗凋亡机制促进细胞存活，靶向抑制NF-KB活性的抗癌药物可以提高化疗的疗效。然而，NF-KB也可以通过抑制细胞存活途径来促进细胞死亡。同样，在侵袭性神经母细胞瘤中经常扩增的N-myc癌基因既能促进细胞存活，也能抑制细胞存活。因此，有效的癌症治疗不能仅仅通过靶向抑制NF-KB或N-mvc来实现。了解NF-KB和N-myc如何通过不同的信号调节来指定靶基因的激活或抑制是至关重要的，从而有助于设计选择性靶向NF-KB和/或N-mvc功能的抗癌药物。

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.