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

中枢神经系统致癌途径中的 NF-kappaB N-myc

基本信息

批准号：
7939233
负责人：
RAQUEL SITCHERAN
金额：
$ 9.97万
依托单位：
TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2011-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7939233
关键词：
Amino Acid Transporter Anchorage-Independent Growth Antineoplastic Agents Apoptosis Biological Biological Models Cell Death Cell Proliferation Cell Survival Complex DNA Data Development Drug Delivery Systems Drug Design Environment Epidermal Growth Factor Excitatory Amino Acids Family member Gene Expression Gene Targeting Genes Genetic Transcription Glutamate Transporter Goals Immunoprecipitation Investigation Knock-out Laboratories MYC gene Malignant - descriptor Malignant Neoplasms Mediating Modeling Molecular Molecular Biology N Domain N-Myc Protein NF-kappa B Neuroblastoma North Carolina Oncogenic Pathogenesis Pathway interactions Pattern Physiological Play Post-Translational Protein Processing Principal Investigator Process Proteins Proteomics RNA Interference Recruitment Activity Repression Research Resistance Role Scientist Signal Transduction Solid Neoplasm Specificity Testing To specify Training Transcriptional Activation Tumor Necrosis Factor-alpha Tumor Necrosis Factors Universities Work base cancer therapy career cell growth chemotherapy design extracellular gene repression improved in vivo insight mouse model neurodevelopment programs promoter protein complex research study response transcription factor tumorigenesis

项目摘要

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.

描述（由申请人提供）：Raquel Sitcheran博士正在北卡罗来纳大学的Albert Baldwin博士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-KB如何响应各种细胞外信号以控制基本过程，例如细胞增殖，凋亡和恶性转化。由于NF-KB可以通过抗脚本机制促进细胞存活，因此靶向抑制NF-KB活性的抗癌药物可以提高化学疗法的疗效。但是，NF-KB还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放大的N-Myc癌基因可以促进和拮抗细胞存活。因此，仅通过靶向抑制NF-KB或N-MVC来实现有效的癌症疗法。了解NF-KB和N-MYC如何通过不同的信号来指定靶基因的激活或抑制，从而有助于选择性地靶向NF-KB和/或N-MVC功能，这一点至关重要。初步数据表明1）NF-KB和N-MYC可以在体内相互作用，而2）N-MYC可以抑制NF-KB的活性。鉴于NF-KB和N-MYC在调节细胞存活和肿瘤发生中起着重要的，有时是相反的作用，Sitcheran博士的直接目标是在使用蛋白质组学，微阵列和鼠标模型系统的使用方面进行额外的培训，以评估NF-KB和N-MYC和NMYC在NFF的机械上的相互作用的生物学意义，以评估NFR的机械性。该建议将阐明NF-KB如何响应多种发育，生理和病理学信号，以指定基因表达的独特模式。将研究以下特定目的：1）NF-KB的表征：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调节的基因； 4）在神经母细胞瘤发病机理中N-MYC和NF-KB之间的合作性分析。这些研究有可能对NF-KB和N-MYC调节的致癌途径的药物设计提供新的见解。