Genetic and Epigenetic Mechanisms of BP Regulation

血压调节的遗传和表观遗传机制

• 批准号: 10023342
• 负责人: MINGYU LIANG
• 金额: $ 237.09万
• 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/10023342
• 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 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.

总体计划摘要 理解血压遗传控制（BP）的最重要的挑战之一是 人类中大多数与BP相关的单核苷酸多态性（SNP）位于非编码中 DNA区域。这些非编码SNP中有许多位于单倍型区域中数千个基本对 远离任何蛋白质编码基因及其对BP的影响，无法通过任何当前已知的编码来解释 或其他功能序列变体，几乎不可能将这些非编码SNP连接到基因或 基于基因组序列调节BP的生理途径。了解基因间的效果 关于基因表达和潜在机制的非编码SNP不仅是BP和 高血压研究，但对于几乎所有复杂性状和常见疾病的研究。 该PPG提案的目标是开始应对这一重大挑战并测试整体 假设非编码SNP与人BP相关，但远离任何蛋白质编码 基因通过表观遗传机制和 这些机制会影响BP。我们开发了三个项目，每个项目都解决了 这个总体假设。项目1将使用精确的基因组编辑来确定特定BP-的影响 相关的非编码SNP关于BP相关的人类细胞类型中的基因表达。项目2将测试 BP相关的非编码SNP会影响BP相关基因的表达的假设 人类细胞中包括染色质循环，增强子功能和非编码RNA的表观遗传机制 和组织。项目3将将这一研究沿体内动物模型进行直接测试 染色质构象在BP调节中起作用的假设。这三个项目将与 彼此广泛告知，并共同实现该计划的总体目标。这三个项目将 依靠核心A进行管理支持和核心B进行测序协调和数据分析。 在过去的几年中，我们至少发表了16篇论文，为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，我们获得了大量 初步数据，以进一步支持各种各样的复杂技术和新技术的可行性 我们将使用拟议的新假设的有效性。该PPG代表了一个从根本上新的方向 进行高血压研究。它将建立几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提高遗传和表观遗传学 高血压和其他疾病地区的研究。