Immunophenotyping of Human Hypertension Using Single Cell Multiplex Mass Cytometry to Identify Novel Therapeutic Targets

使用单细胞多重质谱流式细胞仪对人类高血压进行免疫表型分析，以确定新的治疗靶点

• 批准号: 10000699
• 负责人: Meenakshi Swaminathan Madhur
• 金额: $ 47.1万
• 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: 2021-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10000699
• 关键词: Address; Adult; Age; Aging; Animals; Antibodies; B-Lymphocytes; Blood Pressure; Body mass index; Cells; Chronic; Cytometry; Dialysis procedure; Disease; Exhibits; Functional disorder; Goals; Heart; Heart failure; Human; Hypertension; Immune; Immune system; Immunologics; Immunophenotyping; Immunosuppression; Individual; Inflammation; Inflammatory; Isotopes; Kidney Diseases; Kidney Failure; Lead; Mediating; Morbidity - disease rate; Mus; Myocardial Infarction; Obesity; Organ; Peripheral Vascular Diseases; Population; Production; Public Health; Rare Earth Metals; Residual state; Risk; Rodent; Sorting - Cell Movement; Stimulus; Stroke; T cell receptor repertoire sequencing; T-Lymphocyte; Therapeutic; Time; Widespread Disease; cardiovascular risk factor; cytokine; deep sequencing; extracellular; global health; macrophage; mass spectrometer; monocyte; mortality; new therapeutic target; normotensive; novel; novel diagnostics; novel strategies; peripheral blood; prognostic; response; study population; transcriptome sequencing

PROJECT SUMMARY Hypertension is a major global health concern. In the U.S. alone, one-third of all adults have hypertension and this rises to two-thirds by the age of 60. Hypertension is a key contributor to morbidity and mortality from stroke, myocardial infarction, heart failure, peripheral vascular disease, and renal failure/dialysis. Unfortunately, despite current treatment, blood pressure remains poorly controlled in approximately 50% of individuals with this disease. Even when blood pressure is reasonably controlled, hypertension is associated with increased cardiovascular risk. There is emerging evidence from our lab and others that this residual risk and the end- organ effects of hypertension are largely mediated by inflammation. For example, mice that are deficient in T cells, B cells, monocytes/macrophages, or one of a number of pro-inflammatory cytokines exhibit blunted hypertension and reduced end-organ dysfunction in response to hypertensive stimuli. Yet most of these studies have been conducted in experimental animals, particularly rodents, with limited studies examining the effect of inflammation in human hypertension. Moreover, global or even partial immunosuppression in humans is not without risk. To address this problem, the first goal of this proposal is to utilize a cutting-edge single cell multiplex mass cytometry time of flight (CyTOF) approach to profile the immune cells in the peripheral blood of normotensive and hypertensive humans to identify unique and possibly rare subpopulations that are altered in human hypertension. In mass cytometry, antibodies to extracellular and intracellular targets are conjugated to rare earth metal isotopes that are detected by a mass spectrometer. As obesity and aging are intricately associated with hypertension, our study population will include people with a range of body mass indices and age (35 to 75) to determine the extent to which observed hypertensive changes in immune profiles correlate with obesity and aging. The second goal is to isolate these novel or altered cell populations through flow sorting and further characterize them by RNA-sequencing, cytokine production, and/or deep sequencing of T cell receptors in the case of T lymphocytes. Mapping the immunological landscape of hypertension, obesity, and aging promises to lead to new diagnostic, prognostic, and therapeutic strategies to treat human hypertension and limit the associated end-organ damage from this chronic, widespread disease without inducing global immunosuppression.

项目总结