Genetic and Epigenetic Mechanisms of BP Regulation

总体计划摘要 对于理解血压(BP)的遗传控制来说，最重大的挑战之一是 人类中大多数与BP相关的单核苷酸多态(SNPs)位于非编码区域 DNA的区域。其中许多非编码SNP位于数千个碱基对的单倍型区域 以及它们对BP的影响不能用目前已知的任何编码来解释 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BP的生理途径。了解基因间的影响 非编码SNPs对基因表达及其潜在机制是一个重大挑战，不仅对BP和 高血压的研究，但几乎所有的复杂特征和常见疾病的研究。 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SNPs与人类血压相关，但远离任何编码蛋白质的位置 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BP。我们已经开发了三个项目，每个项目都解决了以下方面 这一总体假设。项目一将使用精确的基因组编辑来确定特定BP的效果- 与BP相关的人类细胞类型中基因表达的相关非编码SNPs。项目2将测试 BP相关非编码SNPs通过影响BP相关基因表达的假说 人类细胞的表观遗传机制包括染色质环、增强子功能和非编码RNA 还有纸巾。项目3将把这一研究路线应用于活体动物模型，以直接测试小说 染色质构象在血压调节中起作用的假说。这三个项目将互动，并 广泛地相互通报，共同实现该计划的总体目标。这三个项目都将 依靠核心A提供行政支持，依靠核心B进行排序协调和数据分析。 在过去的几年里，我们发表了至少16篇论文，为 这种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，以进一步支持广泛的尖端和新技术的可行性 我们将使用和验证提出的新假设.这个PPG代表了一个根本的新方向 用于高血压研究。它将建立几种新的方法和技术，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学和表观遗传学 在高血压和其他疾病领域的研究。

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.