Role of chromatin conformation in BP Regulation

染色质构象在血压调节中的作用

• 批准号: 10023347
• 负责人: Aron M Geurts
• 金额: $ 51.48万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10023347
• 关键词: ATAC-seq; Accounting; Affect; Alleles; Animal Model; Architecture; Base Pairing; Binding; Binding Sites; Blood Pressure; Blood Vessels; CCCTC-binding factor; CRISPR/Cas technology; Cardiovascular Diseases; Catalogs; Cells; Chromatin; Chromatin Structure; Chromosomes; Complex; Conscious; DNA; DNA Binding Domain; DNA-Binding Proteins; Data; Disease; Distal; Encyclopedia of DNA Elements; Endothelium; Engineering; Environment; Epigenetic Process; Event; Gene Expression; Genes; Genetic; Genetic Enhancer Element; Genetic Variation; Genome; Goals; Haplotypes; Heritability; Human; Hypertension; Interruption; Kidney; Laboratories; Lead; Link; Location; Maps; Mediating; Molecular; Molecular Conformation; Mutate; Myocardial Ischemia; Nephrons; Play; Program Research Project Grants; Proteins; Rattus; Reagent; Renin; Research Personnel; Risk Factors; Role; Single Nucleotide Polymorphism; Site; Smooth Muscle Myocytes; Stimulus; Stroke; Techniques; Technology; Testing; Tissues; Untranslated RNA; Variant; Vascular Smooth Muscle; blood pressure regulation; cell type; comparative; data exchange; epigenomics; genetic manipulation; genetic variant; genome wide association study; genome-wide; genomic profiles; in vivo; promoter; response; trait; transcriptome sequencing

PROJECT 3 PROJECT SUMMARY Hypertension remains the most important risk factor for a wide variety of cardiovascular diseases accounting for approximately 54 percent of all strokes and 47 percent of all ischemic heart disease events globally. Despite the fact that we know there is a significant genetic component that determines the level of blood pressure (estimates of heritability for hypertension range from 30-70%) we are far from understanding the myriad of genetic factors that account for blood pressure (BP) variation in humans. One of the most significant challenges for understanding the vast majority of identified BP-associated genetic variations is dissecting the mechanisms of those variants located in regions of DNA that do not encode proteins. In some cases, these variations affect genes that are hundreds of thousands of base pairs away. We believe that some of these genetic variants may affect how the chromosomes are folded in the cell and affect how blood-pressure related genes interact in those folds to control blood pressure. In this project we will focus on testing the specific hypothesis that chromatin conformation and interaction of BP-related genes with their proper regulatory sequences is important in BP regulation. We will use animal models where we genetically disrupt the chromosomes around genes which are known to play a role in blood pressure regulation. We will also use advanced genomic profiling techniques to identify the locations where these interactions occur for tissues such as blood vessels and segments of the nephron of the kidney that are related to BP regulation and use this data to build an `epigenomic' map of chromatin structure, DNA binding proteins, and other features between rats and humans that will allow us to identify and study similar mechanisms for other genes. This project is highly collaborative with the other projects and cores in this Program Project Grant through the sharing of reagents (cells and tissues), transfer of data, and the intellectual environment of the investigators and their laboratories. .

项目3项目摘要 高血压仍然是多种心血管疾病会计的最重要的风险因素 全球所有中风中约有54％和所有缺血性心脏病事件的47％。 尽管我们知道有一个重要的遗传成分决定了血液的水平 压力（高血压遗传力的估计范围为30-70％），我们远没有理解 造成人类血压（BP）变异的无数遗传因素。最重要的之一 理解绝大多数确定的BP相关遗传变异的挑战是剖析 位于不编码蛋白质的DNA区域的那些变体的机制。在某些情况下，这些 变化会影响数十万个碱基对的基因。我们相信其中一些 遗传变异可能会影响细胞中染色体折叠的方式并影响血压相关的方式 基因在这些褶皱中相互作用以控制血压。在这个项目中，我们将专注于测试特定 假设BP相关基因与适当调节的染色质构象和相互作用 序列在BP调节中很重要。我们将使用遗传破坏的动物模型 已知在血压调节中起作用的基因周围的染色体。我们还将使用 先进的基因组分析技术，以识别这些相互作用在组织中发生的位置 作为与BP调节有关的肾脏肾单位的血管和段 构建染色质结构的“表观基因组”图，DNA结合蛋白和大鼠之间的其他特征 和人类，这将使我们能够识别和研究其他基因的类似机制。这个项目高度 通过共享试剂与其他项目和核心合作 （细胞和组织），数据传输以及研究人员及其实验室的智力环境。 。