The overall goal of this Program Project Grant is to understand how immune cells including macrophages, dendritic cells (DCs) and T cells are activated and contribute to cardiovascular diseases including atherosclerosis and hypertension. The major theme is that common insults including atherogenic risk factors, catecholamines, oxidative stress, angiotensin II and excessive salt lead to disregulation of immune cells, leading to local and systemic inflammation. These events promote vascular lesion formation, renal dysfunction, blood pressure elevation and likely other inflammatory processes, common to humans with cardiovascular disease. Project 1 will examine how T cells are activated in hypertension, particularly the role of signals from the central nervous system. Novel mice will be used that allow study of how the sympathetic nervous system stimulates dendritic cells and ultimately T cells. Drs. Harrison and Bernstein have identified an oxidative protein modification that promotes DC immunogenicity. An important collaboration will be to identify specific isoketal adducted peptides in MHC1 that are capable of activating T cells responsible for hypertension. Studies will also address how memory cells participate in hypertension caused by repeated hypertensive stimuli. Studies with Project 3 will examine Studies performed with project 2 will examine epigenetic alterations of T cell subtypes in humans with hypertension. Dr. Cornelia Weyand, the director of project 2 has discovered that macrophages from patients with coronary artery disease or hypertension have a hyperinflammatory phenotype and produce excess IL-1? and IL-6. Together with Core A and Dr. Harrison, Dr. Weyand has shown that reactive oxygen species induce dimerization of PKM2 and its nuclear translocation, where it promotes cytokine production and feed-forward activation of glycolytic flux; a pathology resembling the Warburg effect of cancer cells. This project will define factors that modulate the oligomeric state of PKM2, determine how it leads to cytokine transcription, and examine its role in both atherosclerosis and hypertension. As part of project 2, Dr. Weyand will seek to examine the efficacy of several promising small molecules to normalize function of macrophages from humans with atherosclerosis and hypertension. Dr. Bernstein, the director of project 3, brings to bear his expertise in the biology of the angiotensin I-converting enzyme (ACE). His group will define previously unrecognized roles of ACE in the initiation, maintenance and resolution of inflammation, by modifying cytokine production, antigen presentation in MHC-1 and function of myeloid suppressor cells. Through collaboration with Dr. Markus Kalkum at the City of Hope, Dr. Bernstein will examine how ACE influences the macrophage proteome and peptidome. All projects make use of Core A, which provides expertise in measurement of reactive oxygen species. Overall, this program project grant promises to provide new understanding of the molecular mechanisms of inflammation in cardiovascular diseases and promises to identify new therapeutic targets to reduce morbidity and mortality in these common and devastating illnesses.
Hypertension and atherosclerosis are the major causes of death and disability in Western Societies. Increasing evidence indicates that immunity and inflammation contribute to these diseases, through poorly understood mechanisms. This program project grant will investigate the mechanisms and define new treatments for these disabling diseases.
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