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：
9027422
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/9027422
关键词：
Address Adrenal Glands Affect African African American Aldosterone Alleles 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 Figs - dietary Functional disorder Genes Genetic Genetic Transcription Genotype Heterogeneity Heterozygote Histones Hormones Human Hypertension Hypotension Individual Intake Kidney Knockout Mice Life Light Link Lysine 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 genetic variant high salt diet histone methylation hypertension prevention knock-down normotensive programs public health relevance research study 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（由申请人提供）：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对于迈向更精细的治疗策略（识别特定的“高危”亚群）变得越来越重要。为此，拟议的研究计划重点关注基因转录调节酶赖氨酸特异性脱甲基酶 1 (LSD1) 在连接血压形成的环境调节剂中的作用。我们的初步数据表明，转基因 LSD1 缺陷动物模型表现出对醛固酮表达的日常饮食盐调节的丧失。面对高盐摄入、盐敏感性高血压和血管功能障碍时醛固酮表达升高具有临床相关性，具有 LSD1 多态性变异的人类也表现出与血压和醛固酮改变相关的盐敏感性。然而，只有非裔美国人而非白人表现出这种改变的表型，这些发现导致了这样的假设：LSD1 在将膳食盐与醛固酮作用联系起来方面发挥着作用。LSD1 活性的丧失会导致高盐饮食对醛固酮的通常抑制作用失效。分泌，进而导致血压的盐敏感性和血管功能障碍。以下研究方案将试图证明 LSD1 敲低中存在的醛固酮和血管表型的改变。生命早期的小鼠也见于血压正常的人类（“疾病前”），他们拥有代表 LSD1 功能障碍的“危险”变异等位基因，因为这是处于疾病前状态，我们预计异常表型也存在于小鼠中。然后，我们将证明，由于前者的尿钠排泄能力受损，高血压患者中受影响的 LSD1 基因型对非裔美国人的影响大于白人（我们将进行完整的对抗机制）。严格控制的饮食负荷实验，并按基因型和种族之间的钠排泄能力、血压的盐敏感性、血管结构中LSD1的表达、醛固酮受损和血管反应性进行比较，我们将在我们的动物模型中证明LSD1影响醛固酮合酶的直接证据。表达反过来导致盐敏感性高血压和伴随的血管功能障碍的发生。