The main goal of this Program Project Grant (PPG) is to define the role of hypoxia-elicited elevations of extracellular adenosine and concomitant signaling events in acute versus chronic disease states. Conditions of hypoxia are associated with robust increases in extracellular adenosine. Here, we build on the hypothesis that particularly the AD0RA2B adenosine receptor plays a central role in modulating cellular responses during conditions of hypoxia. During conditions of inflammation, hypoxia, or ischemia, the hypoxia-elicited rise in extracellular adenosine is sufficient to activate the AD0RA2B. This is due to the fact that hypoxia coordinates the transcriptional induction of the AD0RA2B through the activity of hypoxia-inducible factor HIF. Moreover, recent studies have revealed an additional mechanism to enhance AD0RA2B signaling during hypoxia. This involves hypoxia-dependent attenuation of the termination of extracellular adenosine signaling via decreased uptake of extracellular adenosine into the intracellular compartment. This molecular pathway is governed by HIF-dependent repression of adenosine transporters, particularly ENTI and ENT2. All three projects of this PPG focus on hypoxia-elicited increases of extracellular adenosine signaling, including the effects of HIF on AD0RA2B signaling and on ENTs. Therefore, it will be central to the success of the PPG to have state of the art mouse models available to test hypotheses in each individual project. This Transgenic Mouse Breeding Core will provide state of the art mouse models with cell-specific deletions of key genes of the hypoxic adenosine response so that the individual projects can address their hypotheses. The Transgenic Mouse Breeding Core will provide the following services: 1. Generation and initial characterization of transgenic mouse lines with cell-specific deletions of key elements within the hypoxic adenosine response, and 2. Delivery of large breeding stocks of specific mouse lines to the appropriate Project Leaders. Together, these efforts will enhance our knowledge of adenosine and the regulation of disease and move us towards the development of novel therapies to treat various diseases of the lungs and the kidneys.

Public Health Relevance

This Core will provide mice to individual Projects to gain insight into the role of the signaling molecule adenosine in the regulation of deadly lung, kidney and sickle cell disease. This information will benefit the development of novel therapies for these diseases, which are prevalent and deadly.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL114457-02
Application #
8665475
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
2
Fiscal Year
2014
Total Cost
$227,017
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Type
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77225
Kork, Felix; Eltzschig, Holger K (2017) The Devil Is in the Detail: Remote Ischemic Preconditioning for Perioperative Kidney Protection. Anesthesiology 126:763-765
Song, Anren; Zhang, Yujin; Han, Leng et al. (2017) Erythrocytes retain hypoxic adenosine response for faster acclimatization upon re-ascent. Nat Commun 8:14108
Huang, Aji; Wu, Hongyu; Iriyama, Takayuki et al. (2017) Elevated Adenosine Induces Placental DNA Hypomethylation Independent of A2B Receptor Signaling in Preeclampsia. Hypertension 70:209-218
Hoegl, Sandra; Ehrentraut, Heidi; Brodsky, Kelley S et al. (2017) NK cells regulate CXCR2+ neutrophil recruitment during acute lung injury. J Leukoc Biol 101:471-480
Philip, Kemly; Mills, Tingting Weng; Davies, Jonathan et al. (2017) HIF1A up-regulates the ADORA2B receptor on alternatively activated macrophages and contributes to pulmonary fibrosis. FASEB J 31:4745-4758
He, Baokun; Hoang, Thomas K; Wang, Ting et al. (2017) Resetting microbiota by Lactobacillus reuteri inhibits T reg deficiency-induced autoimmunity via adenosine A2A receptors. J Exp Med 214:107-123
Neudecker, Viola; Haneklaus, Moritz; Jensen, Owen et al. (2017) Myeloid-derived miR-223 regulates intestinal inflammation via repression of the NLRP3 inflammasome. J Exp Med 214:1737-1752
Varadarajan, Supraja G; Kong, Jennifer H; Phan, Keith D et al. (2017) Netrin1 Produced by Neural Progenitors, Not Floor Plate Cells, Is Required for Axon Guidance in the Spinal Cord. Neuron 94:790-799.e3
Wirsdörfer, Florian; de Leve, Simone; Cappuccini, Federica et al. (2016) Extracellular Adenosine Production by ecto-5'-Nucleotidase (CD73) Enhances Radiation-Induced Lung Fibrosis. Cancer Res 76:3045-56
Luo, Renna; Liu, Chen; Elliott, Serra E et al. (2016) Transglutaminase is a Critical Link Between Inflammation and Hypertension. J Am Heart Assoc 5:

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