Role of chromatin conformation in BP Regulation

项目3项目总结 高血压仍然是多种心血管疾病最重要的危险因素 全球约54%的中风和47%的缺血性心脏病事件。 尽管我们知道有一种重要的遗传成分决定了血液的水平 血压(对高血压遗传率的估计在30%-70%之间)我们远不能理解 导致人类血压(BP)变化的遗传因素有很多。其中最重要的一个 理解绝大多数已识别的与BP相关的遗传变异的挑战是剖析 这些变异的机制位于DNA中不编码蛋白质的区域。在某些情况下，这些 变异会影响成千上万个碱基对之外的基因。我们认为其中一些 基因变异可能会影响染色体在细胞中的折叠方式，并影响与血压相关的方式 基因在这些折叠中相互作用来控制血压。在本项目中，我们将重点测试特定的 BP相关基因染色质构象及其相互作用与其适当调控的假说 序列在BP调控中起着重要作用。我们将使用动物模型，在这些动物模型中，我们通过基因扰乱 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 先进的基因组图谱技术，以确定这些相互作用发生的组织，如 作为与血压调节有关的肾脏肾单位的血管和节段，并使用该数据 建立大鼠之间染色质结构、DNA结合蛋白和其他特征的表观基因组图谱 以及人类，这将使我们能够识别和研究其他基因的类似机制。这个项目是高度 通过共享试剂与本计划中的其他项目和核心合作项目赠款 (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。 。

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. .