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 nucleltides (such as ATP) and their derivatires 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 cardovascular 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)
Type
Research Program Projects (P01)
Project #
1P01HL120840-01A1
Application #
8787172
Study Section
Heart, Lung, and Blood Program Project Review Committee (HLBP)
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Virginia
Department
Type
DUNS #
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Keller 4th, T C Stevenson; Butcher, Joshua T; Broseghini-Filho, Gilson Brás et al. (2016) Modulating Vascular Hemodynamics With an Alpha Globin Mimetic Peptide (HbαX). Hypertension 68:1494-1503
Penberthy, Kristen K; Ravichandran, Kodi S (2016) Apoptotic cell recognition receptors and scavenger receptors. Immunol Rev 269:44-59
Elliott, Michael R; Ravichandran, Kodi S (2016) The Dynamics of Apoptotic Cell Clearance. Dev Cell 38:147-60
Medina, C B; Ravichandran, K S (2016) Do not let death do us part: 'find-me' signals in communication between dying cells and the phagocytes. Cell Death Differ 23:979-89
Billaud, Marie; Chiu, Yu-Hsin; Lohman, Alexander W et al. (2015) A molecular signature in the pannexin1 intracellular loop confers channel activation by the α1 adrenoreceptor in smooth muscle cells. Sci Signal 8:ra17
Shu, Xiaohong; Keller 4th, T C Stevenson; Begandt, Daniela et al. (2015) Endothelial nitric oxide synthase in the microcirculation. Cell Mol Life Sci 72:4561-75
Arandjelovic, Sanja; Ravichandran, Kodi S (2015) Phagocytosis of apoptotic cells in homeostasis. Nat Immunol 16:907-17
Lohman, Alexander W; Leskov, Igor L; Butcher, Joshua T et al. (2015) Pannexin 1 channels regulate leukocyte emigration through the venous endothelium during acute inflammation. Nat Commun 6:7965
Adamson, Samantha E; Meher, Akshaya K; Chiu, Yu-Hsin et al. (2015) Pannexin 1 is required for full activation of insulin-stimulated glucose uptake in adipocytes. Mol Metab 4:610-8
Good, Miranda E; Begandt, Daniela; DeLalio, Leon J et al. (2015) Emerging concepts regarding pannexin 1 in the vasculature. Biochem Soc Trans 43:495-501

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