Prostate Cancer Risk Enhancers

前列腺癌风险增强剂

• 批准号: 9031723
• 负责人: Gerhard A Coetzee
• 金额: $ 56.49万
• 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: 2010-02-23 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9031723
• 关键词: Affect; Alleles; Binding; Binding Sites; Bioconductor; Bioinformatics; Biotechnology; Cancer Etiology; Cells; Chromatin; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Code; DNA; Data; Data Set; Development; Diabetes Mellitus; Diagnosis; Disease; Engineering; Enhancers; Freezing; Funding; GATA1 gene; Gene Expression; Gene Targeting; Genes; Genetic Predisposition to Disease; Genetic Risk; Genetic Variation; Genetic study; Genomics; Genotype; Genotype-Tissue Expression Project; Grant; Health; Heart Diseases; Housing; In Situ; Individual; LNCaP; Link; Linkage Disequilibrium; Malignant Neoplasms; Malignant neoplasm of prostate; Meta-Analysis; Molecular Conformation; Paper; Persons; Population; Prevention; Preventive; Prostate; Publishing; RNA; Resources; Response Elements; Risk; Sampling; Single Nucleotide Polymorphism; TCF7L2 gene; Techniques; Testing; The Cancer Genome Atlas; Tissue Sample; Untranslated RNA; Work; base; cancer genome; cancer risk; case control; design; follow-up; genetic association; genome editing; genome wide association study; genome-wide; indexing; insight; interdisciplinary approach; novel; risk variant; targeted treatment; tool; transcription factor; transcriptome sequencing

 DESCRIPTION (provided by applicant): This is a revision of a competitive renewal of an existing funded project to identify prostate cancer (PCa) risk enhancers and their target genes. We intend to identify all target genes affected by newly identified enhancers that contain genetic variation at 77 known PCa risk loci. The major `problem' of genome-wide association (GWAS) loci is the lack of mechanistic understanding of how risk alleles function. This is exacerbated by the fact that the vast majority (>90% of PCa risk alleles) resides in non-coding DNA such as enhancers. This application therefore intends to systematically identify target genes of all the newly identified PCa risk enhancers using three independent approaches, formulated here as three specific aims under the auspices of three co-PIs. The three aims are: eQTL (Coetzee) to link SNP genotypes with levels of gene expression genome-wide, CRISPRs (Farnham) to edit enhancers in situ (deletion and allelic replacement) linking them with gene expression and finally 4C (Lu) to match enhancers with potential target genes by chromatin conformation capture. The strength of this plan is that common target genes identified by all three approaches are likely to be functionally significant. Results will elucidate previously unanticipated risk mechanisms and will provide rationale for diagnosis and prevention.

 描述(由申请人提供)：这是一个现有资助项目的竞争性更新的修订版，该项目旨在识别前列腺癌(PCA)风险增强剂及其靶基因。我们打算识别所有受新发现的增强子影响的靶基因，这些增强子在77个已知的PCA风险基因座上包含遗传变异。全基因组关联(GWAS)基因座的主要“问题”是缺乏对风险等位基因如何发挥作用的机械理解。绝大多数(90%的前列腺癌风险等位基因)存在于非编码DNA中，如增强子，这一事实加剧了这种情况。因此，本申请旨在使用三种独立的方法系统地识别所有新发现的PCA风险增强剂的靶基因，在三个共同PIs的主持下，这里将其制定为三个具体目标。这三个目标是：eQTL(Coetzee)将SNP基因型与全基因组的基因表达水平联系起来，CRISPR(Farnham)用于原位编辑增强子(缺失和等位基因替换)，将它们与基因表达联系起来，最后4C(Lu)通过染色质构象捕捉将增强子与潜在的靶基因相匹配。这一计划的优势在于，所有三种方法确定的共同目标基因可能在功能上具有重要意义。结果将阐明以前未预料到的风险机制，并将为诊断和预防提供理论基础。