Epigenetic regulation of aldosterone and salt sensitivity in hypertension

高血压醛固酮和盐敏感性的表观遗传调控

基本信息

批准号：
9211373
负责人：
JONATHAN S. WILLIAMS
金额：
$ 65.7万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-01 至 2021-01-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9211373
关键词：
Address Adrenal Glands Affect African African American Aldosterone Animal Model Biomedical Research Biopsy Blood Pressure Blood Vessels CYP11B2 gene Cardiovascular Diseases Cardiovascular system Categories Caucasians Cell Line Cells Cyclic GMP DNA Data Defect Development Diet Disease Elements Enrollment Environmental Risk Factor Enzymes Epigenetic Process Excretory function Exhibits Functional disorder Genes Genetic Genetic Transcription Genotype Heterogeneity Heterozygote Histones Hormones Human Hypertension Impairment Individual Intake KDM1A gene Kidney Knockout Mice Life Light Link Meta-Analysis Mexican Mineralocorticoid Receptor Modeling Mononuclear Mus Natriuretic Factors Pathway interactions Pharmaceutical Preparations Phenotype Physiological Play Population Protocols documentation Publishing Race Regulation Reporting Research Risk Role Sodium Sodium Chloride Structure Symptoms Syndrome Techniques Variant Vascular Diseases Vasodilation base blood pressure reduction blood pressure regulation chromatin immunoprecipitation clinically relevant dietary control dietary salt epigenetic regulation experimental study genetic variant high salt diet histone methylation hypertension prevention knock-down normotensive programs public health relevance response risk variant salt intake salt sensitive hypertension saluretic screening treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Genetic and environmental factors contribute to the development of cardiovascular diseases. Establishing the relationship between these two factors is of increasing importance in moving towards more refined treatment strategies (identifying specific "at-risk" sub-populations within a disease category, and developing more specific treatment options). To this end, the proposed research program focuses on the role a gene transcription regulating enzyme, Lysine-specific Demethylase 1 (LSD1) plays in linking an environmental modifier of blood pressure (dietary salt) and a key effector enzyme of volume and blood pressure (aldosterone) in the development of hypertension. Our preliminary data demonstrate that a genetically modified LSD1 deficient animal model expresses a loss of usual dietary salt regulation over aldosterone expression. The resultant phenotype is elevated aldosterone expression in the face of high salt intake, salt-sensitive hypertension, and vascular dysfunction. Of clinical relevance, humans with LSD1 polymorphic variation also display an associated salt sensitivity of blood pressure and altered aldosterone responsiveness. However, only African American and not Caucasian display this altered phenotype. These findings led to the hypothesis that LSD1 plays a role in linking dietary salt to aldosterone action. Loss of LSD1 activity disables the usual suppressive actions of a high salt diet on aldosterone secretion, which in turn leads to salt-sensitivity of blood pressure and vascular dysfunction. The following research protocol will seek to demonstrate that the altered aldosterone and vascular phenotypes present in the LSD1 knockdown mouse early in life are also seen in normotensive humans ("pre-disease") who possess the "at risk" variant allele that represents LSD1 dysfunction. Because this is in a pre-disease state, we expect the abnormal phenotype to be present in both races (prior to development of counteracting mechanisms). We will then show that the affected LSD1 genotype in hypertensive individuals affects African Americans more than Caucasians due to impaired natriuretic capacity in the former (an intact counteracting mechanism). We will conduct a strictly controlled dietary loading experiment and compare by genotype and between race sodium excretion capacity, salt sensitivity of blood pressure, expression of LSD1 in vascular structures, impaired aldosterone and vascular responsiveness. We will demonstrate direct evidence in our animal model that LSD1 affects aldosterone synthase expression in turn leading to development of salt-sensitive hypertension and concomitant vascular dysfunction.

描述（由适用提供）：遗传和环境因素有助于心血管疾病的发展。建立这两个因素之间的关系在朝着更精致的治疗策略（确定疾病类别内的特定“处于危险”的亚种群中，并开发更具体的治疗选择）方面越来越重要。为此，拟议的研究计划着重于调节酶的基因转录，赖氨酸特异性去甲基酶1（LSD1）在连接血压环境修饰剂（饮食盐）和关键效应酶体积和血压（aldosterone）中的作用。我们的初步数据表明，一般修饰的LSD1缺陷动物模型表达了对醛固酮表达的通常饮食盐调节的损失。面对高盐的摄入，盐敏感性高血压和血管功能障碍，最终的表型是醛固酮表达升高。临床相关性，具有LSD1多态性变异的人类也表现出血压和醛固酮反应性改变的盐敏感性。但是，只有非裔美国人而不是高加索人表现出这种改变的表型。这些发现导致了以下假设：LSD1在将饮食盐与醛固酮作用联系起来中起作用。 LSD1活性的丧失可以禁用高盐饮食对醛固酮分泌的通常抑制作用，进而导致血压和血管功能障碍的盐敏感性。以下研究方案将试图证明，在正常的潮湿人（“前疾病前”）中还可以看到，LSD1敲低小鼠中存在的醛固酮和血管表型也可见，这些人（“前疾病”）具有代表LSD1功能障碍的“处于危险”变体等位基因。因为这处于疾病前状态，所以我们希望在两个种族中都存在异常的表型（在开发抵消机制之前）。然后，我们将证明高血压个体中受影响的LSD1基因型对非裔美国人的影响比高加索人更大，因为前者的纳地纳特能力受损（一种完整的抵消机制）。我们将进行严格控制的饮食负载实验，并通过基因型进行比较，以及种族钠极端能力，血压的盐敏感性，LSD1在血管结构中的表达，醛固酮受损和血管反应性。我们将在动物模型中证明直接证据表明LSD1影响醛固酮合酶的表达反过来导致盐敏感性高血压和随之而来的血管功能障碍的发展。