A Platform Technology for High-Throughput Screening of Gene Regulatory Elements

基因调控元件高通量筛选平台技术

基本信息

批准号：
9201431
负责人：
GREGORY E CRAWFORD
金额：
$ 22.49万
依托单位：
ELEMENT GENOMICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9201431
关键词：
Acetyltransferase Address Binding Bioinformatics Businesses CRISPR/Cas technology Cardiovascular Diseases Cell Line Cell physiology Cells Chemicals Cholesterol Clinical Trials Design Complex DNA DNA Sequence Alteration DNase I hypersensitive sites sequencing DNase-I Footprinting Data Databases Deoxyribonuclease I Development Diabetes Mellitus Diagnostic Disease Disease susceptibility Drug Design Drug Targeting ERBB2 gene Elements Encyclopedia of DNA Elements Engineering Funding Future Gene Expression Gene Expression Profile Gene Targeting Genes Genetic Genetic Determinism Genetic Variation Genome Genomics Goals Guide RNA Heterogeneity High-Throughput Nucleotide Sequencing Human Human Cell Line Human Genome Human Genome Project Individual Industry Libraries Location Malignant Neoplasms Maps Methods Modeling Mutation Nucleotides Oncogenes Open Reading Frames Patients Performance Pharmaceutical Preparations Pharmacotherapy Phase Phenotype Preclinical Drug Evaluation Proteins RNA Interference Regulatory Element Reporter Reporter Genes Screening Result Signal Pathway Site Small Business Technology Transfer Research Small RNA Sorting - Cell Movement Technology Tissues Transcript Translating United States National Institutes of Health Universities Untranslated RNA Validation Variant Work abstracting base cell type chromosomal location design disease phenotype epigenome epigenomics experience follow-up gene function genome wide association study high throughput analysis high throughput screening human disease human genome sequencing improved innovation interest malignant breast neoplasm nervous system disorder new technology new therapeutic target novel novel therapeutics personalized medicine phase 1 study phase 2 study research study response screening small molecule tool trait transcription factor treatment response

项目摘要

Project Summary/Abstract The goal of this proposal is to develop a novel high-throughput platform for understanding gene regulatory elements in order to identify new drug targets for common diseases. The human genome encodes approximately 50,000 genes. Understanding how those genes are regulated and how this correlates to complex cell phenotypes has long been a major focus of our team. Follow-up projects to the Human Genome Project, such as the NIH-funded Encyclopedia of DNA Elements (ENCODE) and the Roadmap Epigenomics Project, have identified millions of putative regulatory elements across the human genome for many human cell types and tissues. Importantly, genome wide association (GWA) studies have strongly indicated that non- coding regulatory elements determine the gene expression patterns responsible for most complex diseases including cancer, cardiovascular disease, diabetes, and neurological disorders. However, the function of these regulatory elements and their relationships to these disease phenotype are largely unknown. Additionally, conventional screening technologies for perturbing cellular processes, such as small molecules and RNA interference, cannot directly target genomic regulatory elements. To address this critical limitation and illuminate the fundamental genomic basis of these cell phenotypes, we have recently developed epigenome- editing technologies for directly and precisely activating and repressing genomic regulatory elements in their natural chromosomal location. More recently, we have developed a novel and robust method for using these tools for high-throughput identification and quantification of gene regulatory element activity. Here, we propose to apply these methods to the discovery and validation of regulatory elements associated with cancer and cardiovascular disease as demonstration of this novel platform technology for understanding the genetic basis of complex disease. This technology will be critical to translating modern advances in genetics and genomics into new drug targets, diagnostics, and personalized medicine catered to each patient genome.

项目摘要/摘要该提案的目的是开发一个新型的高通量平台，以了解基因调节为了确定常见疾病的新药物目标。人类基因组编码大约50,000个基因。了解这些基因的调节方式以及该基因与长期以来，复杂的细胞表型一直是我们团队的主要重点。人类基因组的后续项目项目，例如NIH资助的DNA元素百科全书（Encode）和路线图表观基因组学项目已经确定了许多人类细胞的人类基因组中数百万个推定的调节元素类型和组织。重要的是，基因组广泛的关联（GWA）研究强烈表明，非 - 编码调节元素决定了负责大多数复杂疾病的基因表达模式包括癌症，心血管疾病，糖尿病和神经系统疾病。但是，这些功能调节元素及其与这些疾病表型的关系在很大程度上是未知的。此外，用于扰动细胞过程的常规筛选技术，例如小分子和RNA 干扰不能直接靶向基因组调节元件。解决此关键限制和阐明了这些细胞表型的基本基因组基础，我们最近发展了表观基因组编辑技术直接，精确激活和抑制其基因组调节元件的编辑技术天然染色体位置。最近，我们开发了一种新颖而强大的方法来使用这些方法用于基因调节元件活性的高通量鉴定和定量的工具。在这里，我们建议将这些方法应用于发现和验证与癌症和心血管疾病作为这种新型平台技术的演示，用于理解遗传基础复杂疾病。这项技术对于翻译遗传学和基因组学的现代进步至关重要进入新的药物靶标，诊断和个性化药物，适合每个患者基因组。