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.

Public Health Relevance

Hypertension is a leading cause of worldwide morbidity and mortality and a key contributor to heart, vessel, and kidney disease. These effects of hypertension are largely mediated by a dysregulated immune system. This project will use a novel approach to identify and characterize the specific changes that occur in the immune system during human hypertension, thus leading to novel therapeutic targets and treatment approaches to modulate the immune system without causing global immunosuppression.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
NIH Director’s New Innovator Awards (DP2)
Project #
1DP2HL137166-01
Application #
9166681
Study Section
Special Emphasis Panel (ZRG1-MOSS-C (56)R)
Program Officer
OH, Youngsuk
Project Start
2016-09-30
Project End
2021-06-30
Budget Start
2016-09-30
Budget End
2021-06-30
Support Year
1
Fiscal Year
2016
Total Cost
$2,355,000
Indirect Cost
$855,000
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
079917897
City
Nashville
State
TN
Country
United States
Zip Code
37232
Tong, Carl W; Madhur, Meena S; Rzeszut, Anne K et al. (2017) Status of Early-Career Academic Cardiology: A Global Perspective. J Am Coll Cardiol 70:2290-2303
Norlander, Allison E; Saleh, Mohamed A; Pandey, Arvind K et al. (2017) A salt-sensing kinase in T lymphocytes, SGK1, drives hypertension and hypertensive end-organ damage. JCI Insight 2: