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

我是国家医学图书馆分子生物物理系博士后研究员 耶鲁大学生物化学专业。有了这个培训/研究建议，我正在申请这份工作 发展奖。我获得了生物学和计算机科学的学位，并开始了我的 1998年，我的研究兴趣领域--计算生物学的培训和研究。我的直系亲属 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调查员，并使 在与健康相关的研究领域做出了重大贡献。为了实现这些目标，我将首先进行辅导 在耶鲁大学Gerstein和Snyder教授的指导下进行功能基因组学研究两年 然后申请另一所大学的研究职位。 我提出的研究的目标是获得和分析基因表达、转录 调控和DNA拷贝数变化与肿瘤转移进展的关系 研究计划。这项建议基于我在微阵列数据基因组分析方面的经验，这是 Encode项目。对于培训补助金，拟议的研究项目包括试验性和 计算组件。具体地说，我建议确定两个关键调控因子的DNA结合位点 正常小鼠胚胎细胞和4个小鼠等基因小鼠的肿瘤转移(Twist和Snail) 乳腺癌细胞系(67NR、168FARN、4T07、4T1)。同时，我将开发新的算法 用于分析扰动的基因表达谱以构建特定于EMT的调节子网络 为进一步的ChlP芯片实验处理和确定其他EMT调节器。作为该基因的靶基因 已识别的EMT调节子可能会因染色体微重排而复制或缺失 在肿瘤转移期间，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。 我觉得这项拟议的研究与公共健康非常相关，因为癌症约占25% 在美国所有的死亡人数中。然而，90%的人类癌症死亡可以归因于转移， 在此期间，肿瘤细胞从原发肿块扩散到远处的器官。显然，这是非常重要的 了解是什么使癌症转移成为可能，并解开其分子机制。

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.