Deep phenotypic and functional characterization of salt-responsive immune cells in human salt senstive hypertension using CTE-seq

使用 CTE-seq 对人类盐敏感性高血压中的盐反应性免疫细胞进行深度表型和功能表征

• 批准号: 10337042
• 负责人: Annet Kirabo
• 金额: $ 8.65万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10337042
• 关键词: Affect; Antibodies; Antigen-Presenting Cells; Antigens; Blood; Blood Glucose; Blood Pressure; Brain; Cardiovascular Diseases; Cardiovascular system; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Cessation of life; Cholesterol; Consumption; Data; Dendritic Cells; Dendritic cell activation; Diagnosis; Disease; Environment; Event; Excess Dietary Salt; Excretory function; Exhibits; Extracellular Fluid; Gene Expression; Genes; Hour; Human; Hypertension; Hypotension; Immune; In Vitro; Individual; Inflammation; Injury to Kidney; Intake; Interleukin-1; Interleukin-1 beta; Interleukin-6; Kidney; Laboratories; Lead; Lipid Peroxidation; Lipids; Location; Lysine; Mendelian disorder; Modeling; Myelogenous; NADPH Oxidase; Oligonucleotides; Organ; Participant; Pathogenesis; Pattern; Persons; Phenotype; Plasma; Play; Population; Production; Proteins; Pulse Pressure; Regulation; Research; Resistance; Role; Site; Sodium; Sodium Channel; Sodium Chloride; T Chain; T-Cell Receptor; T-Lymphocyte; TNF gene; Techniques; Testing; Time; Tissues; Variant; adduct; blood pressure elevation; cardiovascular risk factor; cost; cost effective; cytokine; dietary salt; epithelial Na+ channel; extracellular; gain of function; high body mass index; hypertensive; immune activation; immunogenic; in vivo; innovation; interstitial; ketoaldehyde; loss of function; loss of function mutation; monocyte; normotensive; oxidation; personalized diagnostics; personalized medicine; response; salt intake; salt sensitive; salt sensitive hypertension; tool

Project Summary: Salt-sensitive hypertension is an independent predictor of death due to cardiovascular disease (CVD), but the mechanisms are poorly understood. Most of the research on salt-sensing mechanisms has focused on the kidney, the vasculature and the brain; however, recent studies from our laboratory have found that immune cells including antigen presenting cells (APCs) can sense sodium (Na+) and contribute to salt-induced hypertension and end organ damage through a mechanism involving increased lipid oxidation and formation of immunogenic gamma ketoaldehydes known as isolevuglandins (IsoLGs) or isoketals. Emerging evidence suggests that Na+ accumulates in the interstitium and activates immune cells but the specific tissue location including the origin, antigenic site, and final target for salt-activated immune cell in cardiovascular tissues is not known. Tools to study T cells have been rapidly expanding over the past 5 years along with increased computing capacity including single T cells sequencing of α and β chain T cell receptor spectra typing but very few studies have investigated APCs using these advanced techniques and we do not know where or how they are activated and in turn activate T cells in salt-induced CVD. We propose an innovative approach to use 5’ CITE-Seq and post hoc sequencing, to phenotype APCs in people with salt-sensitivity of blood pressure. We will couple the immune phenotype with IsoLG formation using our innovative approach to conjugate the anti- IsoLG D11 ScFv antibody sequence with an oligo and use CITE-Seq to track these important activated IsoLG-positive cells and determine if these are associated with gene expression of sodium channels. Identifying the immune cells associated with salt-sensitivity of blood pressure will have a far-ranging impact on our understanding of the pathogenesis of salt-induced hypertension and other diseases aggravated by high salt consumption.

项目总结: