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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.