Genetic and Epigenetic Mechanisms of BP Regulation

血压调节的遗传和表观遗传机制

• 批准号: 10460342
• 负责人: MINGYU LIANG
• 金额: $ 235.69万
• 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 2023-06-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10460342
• 关键词: Address; Animal Model; Area; Base Pairing; Biological; Blood Pressure; Blood Vessels; Cells; Cessation of life; Characteristics; Chromatin; Chromatin Loop; Code; Complex; DNA; Data; Data Analyses; Data Set; Development; Disease; Enhancers; Epigenetic Process; Gene Expression; Gene Expression Profiling; Genes; Genetic; Genomics; Goals; Haplotypes; Human; Human Genome; Hypertension; Kidney; Knowledge; Link; Maps; Mediating; Modeling; Molecular Conformation; Nephrons; Paper; Pathway interactions; Physiological; Play; Proteins; Publishing; Rattus; Renin; Research; Research Personnel; Resistance; Risk Factors; Role; Single Nucleotide Polymorphism; Testing; Tissues; Untranslated RNA; Variant; arteriole; base; blood pressure control; blood pressure regulation; burden of illness; cell type; epigenetic regulation; epigenome; experimental study; genome editing; human tissue; in vivo Model; induced pluripotent stem cell; insight; new technology; novel; novel strategies; programs; stem cells; trait

OVERALL PROGRAM SUMMARY One of the most significant challenges for understanding genetic control of blood pressure (BP) is that the vast majority of BP-associated single nucleotide polymorphisms (SNPs) in humans are located in noncoding regions of DNA. Many of these noncoding SNPs are located in haplotype regions thousands of base pairs away from any protein-coding gene and their effects on BP cannot be explained by any currently known coding or other functional sequence variant, making it nearly impossible to link these noncoding SNPs to genes or physiological pathways that regulate BP based on genomic sequence. Understanding the effect of intergenic noncoding SNPs on gene expression and the underlying mechanisms is a major challenge not just for BP and hypertension research, but for research on nearly all complex traits and common diseases. The goal of this PPG proposal is to begin to address this major challenge and test the overall hypothesis that noncoding SNPs associated with human BP but located far from any protein-coding gene regulate gene expression in specific BP relevant cell types through epigenetic mechanisms and these mechanisms can influence BP. We have developed three projects that each address one aspect of this overall hypothesis. Project 1 will use precision genome editing to identify the effect of specific BP- associated noncoding SNPs on gene expression in BP-relevant human cell types. Project 2 will test the hypothesis that BP-associated noncoding SNPs influence the expression of BP-relevant genes through epigenetic mechanisms including chromatin looping, enhancer function and noncoding RNA in human cells and tissues. Project 3 will take this line of research to animal models in vivo to test directly the novel hypothesis that chromatin conformation plays a role in BP regulation. The three projects will interact with, and inform, each other extensively and, together, will achieve the overall goal of the program. All three projects will rely on Core A for administrative support and Core B for sequencing coordination and data analysis. We have published at least 16 papers in the last few years that provide direct support for key aspects of the conceptual validity and technical feasibility of this PPG. In addition, we have obtained a large amount of preliminary data to further support the feasibility of the wide range of sophisticated and new technologies that we will use and the validity of proposed novel hypotheses. This PPG represents a fundamentally new direction for hypertension research. It will establish several novel approaches and technologies, generate unique and extensive datasets, and provide new biological insights, all of which will help to advance genetic and epigenetic research in hypertension and other disease areas.

总体计划概要 了解血压 (BP) 基因控制的最重大挑战之一是，大量的 人类中大多数与 BP 相关的单核苷酸多态性 (SNP) 位于非编码位点 DNA 区域。许多非编码 SNP 位于单倍型区域的数千个碱基对中 远离任何蛋白质编码基因，其对血压的影响无法用任何目前已知的编码来解释 或其他功能序列变体，使得几乎不可能将这些非编码 SNP 与基因或 基于基因组序列调节血压的生理途径。了解基因间的影响 基因表达的非编码 SNP 及其潜在机制不仅对 BP 和 高血压研究，但用于几乎所有复杂特征和常见疾病的研究。 本 PPG 提案的目标是开始解决这一重大挑战并测试整体 假设非编码 SNP 与人类 BP 相关，但远离任何蛋白质编码 基因通过表观遗传机制调节特定 BP 相关细胞类型的基因表达 这些机制可以影响血压。我们开发了三个项目，每个项目都解决一个方面 这个总体假设。项目1将使用精确基因组编辑来识别特定BP-的影响 BP相关人类细胞类型中基因表达的相关非编码SNP。项目2将测试 假设 BP 相关非编码 SNP 通过以下方式影响 BP 相关基因的表达： 表观遗传机制，包括人类细胞中的染色质环、增强子功能和非编码 RNA 和纸巾。项目3将把这方面的研究应用于动物模型体内，以直接测试该小说 染色质构象在血压调节中发挥作用的假设。这三个项目将相互作用，并且 广泛地相互通报，共同实现该计划的总体目标。所有三个项目都将 依靠核心 A 提供管理支持，依靠核心 B 进行排序协调和数据分析。 过去几年我们发表了至少 16 篇论文，为以下关键方面提供了直接支持： 该 PPG 的概念有效性和技术可行性。此外，我们还获得了大量的 初步数据进一步支持各种复杂和新技术的可行性 我们将使用和验证所提出的新假设的有效性。这个 PPG 代表了一个全新的方向 用于高血压研究。它将建立多种新颖的方法和技术，产生独特的和 广泛的数据集，并提供新的生物学见解，所有这些都将有助于推进遗传和表观遗传 主要从事高血压及其他疾病领域的研究。