Communication between cells within a tissue environment is fundamentally important for many physiological processes. Working in the context of how apoptotic cells are removed by phagocytes within tissues, we initially observed that nucleotides such as ATP and UTP released from apoptotic cells via Pannexin-1 (Panx1) channels and act as ?find-me signals? to attract phagocytes, leading to the prompt removal of corpses. Subsequent work (in collaboration with the other three Project leaders) identified a caspase-dependent cleavage of the C-terminus of Panx1 as one of the mechanisms of Panx1 channel opening. In the past few years, directly via Project 1, we have made several key observations that form the basis of this current renewal. These include the identification of a new Panx1 channel inhibitor trovafloxacin and demonstrating a novel role for Panx1 in apoptosis (Poon et al., Nature 2014); identifying spironolactone as a new inhibitor of Panx1 and demonstrating the importance spironolactone mediated Panx1 inhibition in regulating blood pressure spironolactone (Good et al., Circ Research 2017); identified a new activator of Panx1; generating a new transgenic mouse capable of inducibly overexpressing Panx1; and, identification of new binding partners of Panx1 (kinase SIK) via a two-hybrid screen. Project 1 has also generated a number of new mouse tools that are widely used by other members of the PPG. In this Project 1, we aim to test the central hypothesis that Panx1 controls inflammatory processes through purinergic as well as non-purinergic signals, fundamentally shifting the current perspective on Panx1.
In Aim 1, we will test a new concept (from our preliminary studies) that Panx1 channels can release both purinergic and non-purinergic metabolites that influence inter-cellular communication directly, and the anti-inflammatory tone within the local tissue milieu. We will also test the role of a newly identified Panx1 agonist methoctramine, and whether this can also influence the release of novel metabolites via Panx1.
In Aim 2, based on our preliminary studies that Panx1 channels are required for limiting airway inflammation, we will test the role of Panx1 in airway disease using models we have recently established (Han et al., Nature 2016). Further, based on the new Panx1 interacting partner SIK that we identified, we will probe the mechanistic aspects of Panx1 requirement in airway inflammation. Collectively, we expect these studies to provide new insights on how pannexin channels function in different contexts in vivo, identify new modes of stimulating Panx1 function, and better define Panx1- dependent intercellular communication toward regulating the inflammatory tone in tissues. The new mouse lines, small molecule modulators, and protein interactors identified by Project 1 will integrate seamlessly with the other three projects and cores within this P01.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL120840-06
Application #
9633556
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
OH, Youngsuk
Project Start
Project End
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
6
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Virginia
Department
Type
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
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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
Kerur, Nagaraj; Fukuda, Shinichi; Banerjee, Daipayan et al. (2018) cGAS drives noncanonical-inflammasome activation in age-related macular degeneration. Nat Med 24:50-61
Morioka, Sho; Perry, Justin S A; Raymond, Michael H et al. (2018) Efferocytosis induces a novel SLC program to promote glucose uptake and lactate release. Nature 563:714-718

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