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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas Health Science Center Houston
United States
Zip Code
Neudecker, Viola; Brodsky, Kelley S; Kreth, Simone et al. (2016) Emerging Roles for MicroRNAs in Perioperative Medicine. Anesthesiology 124:489-506
Garcia-Morales, Luis J; Chen, Ning-Yuan; Weng, Tingting et al. (2016) Altered Hypoxic-Adenosine Axis and Metabolism in Group III Pulmonary Hypertension. Am J Respir Cell Mol Biol 54:574-83
Hoegl, Sandra; Zwissler, Bernhard; Eltzschig, Holger K et al. (2016) Acute respiratory distress syndrome following cardiovascular surgery: current concepts and novel therapeutic approaches. Curr Opin Anaesthesiol 29:94-100
Baudiß, Kristin; de Paula Vieira, Rodolfo; Cicko, Sanja et al. (2016) C1P Attenuates Lipopolysaccharide-Induced Acute Lung Injury by Preventing NF-κB Activation in Neutrophils. J Immunol 196:2319-26
Goodman, Steven R; Pace, Betty S; Hansen, Kirk C et al. (2016) Minireview: Multiomic candidate biomarkers for clinical manifestations of sickle cell severity: Early steps to precision medicine. Exp Biol Med (Maywood) 241:772-81
Wu, Hongyu; Bogdanov, Mikhail; Zhang, Yujin et al. (2016) Hypoxia-mediated impaired erythrocyte Lands' Cycle is pathogenic for sickle cell disease. Sci Rep 6:29637
Dehn, Shirley; DeBerge, Matthew; Yeap, Xin-Yi et al. (2016) HIF-2α in Resting Macrophages Tempers Mitochondrial Reactive Oxygen Species To Selectively Repress MARCO-Dependent Phagocytosis. J Immunol 197:3639-3649
Ju, Cynthia; Colgan, Sean P; Eltzschig, Holger K (2016) Hypoxia-inducible factors as molecular targets for liver diseases. J Mol Med (Berl) 94:613-27
Luo, Fayong; Le, Ngoc-Bao; Mills, Tingting et al. (2016) Extracellular adenosine levels are associated with the progression and exacerbation of pulmonary fibrosis. FASEB J 30:874-83
Kiers, Harmke D; Scheffer, Gert-Jan; van der Hoeven, Johannes G et al. (2016) Immunologic Consequences of Hypoxia during Critical Illness. Anesthesiology 125:237-49

Showing the most recent 10 out of 43 publications