Inter-cellular communication between cells within a tissue environment is fundamentally important for many physiological processes. Channels and transmembrane transporters that conduct ions and other molecules across the plasma membrane in healthy living cells are also linked to pathologies of the cardiovascular and respiratory systems. Extracellular nucleotides (such as ATP) and their derivatives critically influence many aspects of vascular physiology such as vasoconstriction and blood pressure regulation, as well disease states such as metabolic syndromes. Recent exciting series of observations suggest that the pannexin proteins form channels on the plasma membrane, and by permeating ions and/or the release of nucleotides in a very regulated manner, these pannexin channels allow cells to communicate with other cells. Consistent with this, altered expression of pannexin channels have been linked to cardiovascular and metabolic disorders. On an independent and inter-related set of observations, the pannexin channels also play a role in releasing nucleotides from early stage apoptotic cells that appear critical for communicating with phagocytes and in turn promoting prompt corpse removal. Since, failed clearance of dying cells is linked to atherosclerosis and airway inflammation, pannexin channels likely also play a role in regulating inflammation within tissues. The central hypothesis tested via this P01 application is that pannexin channels sit at a critical interphase between normal homeostasis within the cardiovascular system, and the disease states leading inflammation, atherosclerosis, and hypertension. The four projects that comprise this proposal address the role of pannexin channels as follows. Project 1 (Ravichandran) addresses the role of pannexin channels in cell death and recruitment of monocytes during atherosclerosis, cholesterol efflux, and in tissue inflammation;Project 2 (Isakson) addresses how pannexin channels in smooth muscle cells contribute to vasoconstriction in resistance vessels to regulate blood pressure and how this is altered in obesity;Project 3 (Leitinger) addresses how pannexin channels regulate adipocyte functions and the inflammation induced by dying adipocytes in obesity, insulin resistance and hypertension;Project 4 (Bayliss) addresses molecular mechanisms of pannexin channel activation in physiological and diseased states. With the combination of mouse models and ex vivo studies, and mechanistic approaches, and the preliminary identification of new compounds capable of altering Panx1 function, we expect to provide exciting new insights on pannexin channels and purinergic signaling in vascular physiology and hypertension, and provide the basis for novel treatment strategies targeting the regulated opening and closing of these channels in specific disease states. We expect this would have a broad impact to cardiovascular, metabolic, and respiratory diseases.

Public Health Relevance

Overall Program Project - Project Narrative Signaling via extracellular nucleotides (purinergic signaling) critically regulates vascular physiology and inflammation in tissues. One mode by which cells release nucleotides is via the newly discovered pannexin channels. Recent genome wide expression analyses have linked altered expression of Pannexin 1 to atherosclerosis, vascular disease, and airway inflammation. Therefore, the studies of this P01 project are expected to mechanistically define the specific roles played by the pannexin channels in vascular and adipose tissue inflammation, and in turn, identify potential points for therapeutic targeting of these channels in these human diease conditions.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
1P01HL120840-01A1
Application #
8742058
Study Section
Heart, Lung, and Blood Program Project Review Committee (HLBP)
Program Officer
OH, Youngsuk
Project Start
2014-08-01
Project End
2019-05-31
Budget Start
2014-08-01
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Virginia
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Penberthy, Kristen K; Lysiak, Jeffrey J; Ravichandran, Kodi S (2018) Rethinking Phagocytes: Clues from the Retina and Testes. Trends Cell Biol 28:317-327
Chiu, Yu-Hsin; Schappe, Michael S; Desai, Bimal N et al. (2018) Revisiting multimodal activation and channel properties of Pannexin 1. J Gen Physiol 150:19-39
DeLalio, Leon J; Keller, Alexander S; Chen, Jiwang et al. (2018) Interaction Between Pannexin 1 and Caveolin-1 in Smooth Muscle Can Regulate Blood Pressure. Arterioscler Thromb Vasc Biol 38:2065-2078
Nyberg, Michael; Piil, Peter; Kiehn, Oliver T et al. (2018) Probenecid Inhibits ?-Adrenergic Receptor-Mediated Vasoconstriction in the Human Leg Vasculature. Hypertension 71:151-159
Serbulea, Vlad; Upchurch, Clint M; Ahern, Katelyn W et al. (2018) Macrophages sensing oxidized DAMPs reprogram their metabolism to support redox homeostasis and inflammation through a TLR2-Syk-ceramide dependent mechanism. Mol Metab 7:23-34
Good, Miranda E; Chiu, Yu-Hsin; Poon, Ivan K H et al. (2018) Response by Good et al to Letter Regarding Article, ""Pannexin-1 Channels as an Unexpected New Target of the Antihypertensive Drug Spironolactone"". Circ Res 122:e88-e89
Schappe, Michael S; Szteyn, Kalina; Stremska, Marta E et al. (2018) Chanzyme TRPM7 Mediates the Ca2+ Influx Essential for Lipopolysaccharide-Induced Toll-Like Receptor 4 Endocytosis and Macrophage Activation. Immunity 48:59-74.e5
Good, Miranda E; Chiu, Yu-Hsin; Poon, Ivan K H et al. (2018) Pannexin 1 Channels as an Unexpected New Target of the Anti-Hypertensive Drug Spironolactone. Circ Res 122:606-615
Serbulea, Vlad; Upchurch, Clint M; Schappe, Michael S et al. (2018) Macrophage phenotype and bioenergetics are controlled by oxidized phospholipids identified in lean and obese adipose tissue. Proc Natl Acad Sci U S A 115:E6254-E6263
Adamson, Samantha E; Montgomery, Garren; Seaman, Scott A et al. (2018) Myeloid P2Y2 receptor promotes acute inflammation but is dispensable for chronic high-fat diet-induced metabolic dysfunction. Purinergic Signal 14:19-26

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