Biological Studies

生物学研究

• 批准号: 7933386
• 负责人: BRIAN E HENDERSON
• 金额: $ 62.04万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7933386
• 关键词: Address; Alleles; Alternative Splicing; Androgen Receptor; Area; Automobile Driving; Biological; Biological Assay; Biology; Cancer Biology; Candidate Disease Gene; Cataloging; Catalogs; Cell Line; Censuses; Characteristics; Chromatin; Chromosomes; Code; Deoxyribonucleases; Disease; EP300 gene; Elements; Enhancers; Epigenetic Process; Functional RNA; Gene Expression; Gene Expression Profile; Gene Targeting; Genes; Genetic; Genome; Genomics; Goals; Histologic; Human Genetics; Hypersensitivity; Inherited; Intervention; Knowledge; Lasers; Lead; Link; Luciferases; Malignant Neoplasms; Malignant neoplasm of prostate; Maps; Methods; MicroRNAs; Molecular Conformation; Open Reading Frames; Other Genetics; Pathogenesis; Pathway interactions; Prevention; Prostate; Prostatic Neoplasms; Proteins; Regulatory Element; Risk; Site; Techniques; Testing; Tissues; Transcript; Tumor Tissue; Variant; base; cancer risk; chromatin immunoprecipitation; disorder prevention; gene discovery; genetic association; genome wide association study; insight; novel; overexpression; prevent; promoter; research study; sound; tumorigenesis

Project Summary: The ultimate goal of project 2 is the discovery of the genes that drive prostate cancer pathogenesis. Since most of the risk variants discovered to date reside outside of known protein coding regions (i.e., intronic and intergenic), systematic approaches are required to reveal the connection between the risk allele and the gene that it influences. The primary hypotheses that we are comprehensively testing are that the risk regions harbor an as yet undiscovered transcript and/or that the risk regions are functional elements (e.g., promoters and enhancers) that influence gene expression. A range of complementary techniques is proposed that will thoroughly address these hypotheses. The prostate transcriptome will be sequenced to derive an unbiased census of coding and non-coding transcripts and alternative splicing. Functionally relevant elements within the prostate cancer risk loci regions will be annotated using the techniques of chromatin immunoprecipitation and DNase hypersensitivity. Finally, methods will be employed to functionally characterize each of the risk loci, including chromosome conformation capture to identify all other genomic regions that are interacting with the risk region, gene perturbation (e.g., knockdown and overexpression) experiments of candidate genes surrounding the risk regions, and evaluating associations between the risk alleles and transcript abundance across candidate genes. Understanding the biologic pathways driving prostate cancer provides a sound basis for rational intervention in disease prevention and treatment.

项目摘要： 项目2的最终目标是发现驱动前列腺癌发病机制的基因。以来 迄今为止发现的大多数风险变体位于已知蛋白质编码区之外（即，内含子和 基因间），需要系统的方法来揭示风险等位基因和基因之间的联系 它所影响的。我们正在全面检验的主要假设是， 尚未发现的转录本和/或风险区是功能元件（例如，启动子和 增强子）影响基因表达。提出了一系列补充技术， 彻底解决这些假设。将对前列腺转录组进行测序，以获得无偏倚的 编码和非编码转录本和可变剪接的普查。在职能上相关的要素 将使用染色质免疫沉淀技术注释前列腺癌风险基因座区域， DNA酶超敏反应。最后，将采用方法来功能性地表征每个风险位点， 包括染色体构象捕获以鉴定与所述基因组相互作用的所有其它基因组区域。 风险区域，基因扰动（例如，敲低和过表达）实验 围绕风险区域，并评估风险等位基因和转录本丰度之间的关联 跨候选基因。了解驱动前列腺癌的生物学途径提供了坚实的基础 合理干预疾病防治。