Gene regulation in metastasis and new methods to analyze its microarray profiles

描述(由申请人提供)： 我是耶鲁大学分子生物物理和生物化学系国家医学图书馆的博士后研究员。有了这个培训/研究建议，我正在申请职业发展奖。我获得了生物学和计算机科学的学位，并于1998年开始了我的计算生物学培训和研究，这是我的研究兴趣领域。我的直接职业目标是在功能基因组学方面进行广泛的培训，包括计算和实验。我的长期职业目标是成为一名研究机构的独立研究员，为健康相关研究领域做出实质性贡献。为了实现这些目标，我将首先在耶鲁大学Gerstein和Snyder教授的指导下进行为期两年的功能基因组学指导研究，然后申请另一家机构的研究职位。 我建议的研究的目标是获得和分析与肿瘤转移进展相关的基因表达、转录调控和DNA拷贝数变化的图谱，作为五年研究计划的一部分：这项建议建立在我作为ENCODE项目的一部分对微阵列数据进行基因组分析的经验基础上。对于培训补助金，拟议的研究项目既包括实验部分，也包括计算部分。具体地说，我建议在正常小鼠胚胎细胞和四个小鼠等基因乳腺癌细胞系(67NR、168FARN、4T07和4T1)中确定两个肿瘤转移关键调节因子(Twist和Snail)的DNA结合位点。同时，我将开发新的算法来分析扰动的基因表达谱，以建立一个特定于EMT过程的调节子网络，并为进一步的ChlP-ChIP实验确定其他EMT调节子。由于已识别的EMT调控因子的靶基因可能会在肿瘤转移过程中由于染色体微重排而复制或缺失，因此我还将进行计算研究，以分析基于阵列的比较基因组杂交数据，以识别这种DNA拷贝数变异。 我认为这项拟议的研究与公共健康非常相关，因为癌症占美国所有死亡人数的25%左右。然而，90%的人类癌症死亡可以归因于转移，在转移期间，肿瘤细胞从原发肿瘤块扩散到远处的器官。显然，了解是什么使癌症转移成为可能并解开其分子机制是非常重要的。

DESCRIPTION (provided by applicant): I am a National Library of Medicine research postdoctoral fellow in the Department of Molecular Biophysics and Biochemistry at Yale University. With this training/research proposal, I am applying to the Career Development Award. I had degreed education in both Biology and Computer Science and started my training and research in Computational Biology, the field of my research interest, in 1998. My immediate career goal is to have an extensive training in functional genomics, both computational and experimental. My long-term career goal is to become an independent investigator at a research institution and to make a substantial contribution to health-related research field. To achieve these goals, I will first conduct mentored research in functional genomics for two years under the guidance of Profs Gerstein and Snyder at Yale University and then apply for a research position at another institution. The goal of my proposed research is to obtain and analyze the profiles of gene expression, transcription regulation, and DNA copy number variation related to tumor metastasis progression as the five-year Research Plan: This proposal builds on my experience in genomic analysis of microarray data as a part of the ENCODE Project. For a training grant, the proposed research projects include both experimental and computational components. Specifically, I propose to identify the DNA-binding sites of two key regulators of tumor metastasis (Twist and Snail) in both normal murine embryonic cells and four murine isogenic mammary carcinoma cell lines (67NR, 168FARN, 4T07, and 4T1). In parallel, I will develop new algorithms for analyzing perturbed gene expression profiles to build a regulatory sub-network specific to the EMT process and identify other EMT regulators for further ChlP-chip experiments. As the target genes of the identified EMT regulators could be duplicated or deleted as a result of chromosomal micro-rearrangements during tumor metastasis, I will also carry out computational studies to analyze array-based comparative genomic hybridization data to identify such DNA copy number variations. I feel the proposed research is quite relevant to public health, becaus cancer is responsible for about 25% of all deaths in the United States. 90% of human cancer deaths, however, can be attributed to metastases, during which tumor cells spread from the primary tumor mass to distant organs. Clearly it is very important to understand what makes metastasis possible for a cancerous tumor and unravel its molecular mechanism.