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)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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University of Texas Health Science Center Houston
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Aherne, Carol M; Collins, Colm B; Rapp, Caroline R et al. (2018) Coordination of ENT2-dependent adenosine transport and signaling dampens mucosal inflammation. JCI Insight 3:
Mertens, Tinne C J; Hanmandlu, Ankit; Tu, Ly et al. (2018) Switching-Off Adora2b in Vascular Smooth Muscle Cells Halts the Development of Pulmonary Hypertension. Front Physiol 9:555
Bowser, Jessica L; Phan, Luan H; Eltzschig, Holger K (2018) The Hypoxia-Adenosine Link during Intestinal Inflammation. J Immunol 200:897-907
Lim, Grace; Facco, Francesca L; Nathan, Naveen et al. (2018) A Review of the Impact of Obstetric Anesthesia on Maternal and Neonatal Outcomes. Anesthesiology 129:192-215
Kiers, Dorien; Wielockx, Ben; Peters, Esther et al. (2018) Short-Term Hypoxia Dampens Inflammation in vivo via Enhanced Adenosine Release and Adenosine 2B Receptor Stimulation. EBioMedicine 33:144-156
Zhao, Shushan; Adebiyi, Morayo G; Zhang, Yujin et al. (2018) Sphingosine-1-phosphate receptor 1 mediates elevated IL-6 signaling to promote chronic inflammation and multitissue damage in sickle cell disease. FASEB J 32:2855-2865
Hadi, Tarik; Boytard, Ludovic; Silvestro, Michele et al. (2018) Macrophage-derived netrin-1 promotes abdominal aortic aneurysm formation by activating MMP3 in vascular smooth muscle cells. Nat Commun 9:5022
Yuan, Xiaoyi; Lee, Jae W; Bowser, Jessica L et al. (2018) Targeting Hypoxia Signaling for Perioperative Organ Injury. Anesth Analg 126:308-321
Liu, Hong; Adebiyi, Morayo; Liu, Rong Rong et al. (2018) Elevated ecto-5'-nucleotidase: a missing pathogenic factor and new therapeutic target for sickle cell disease. Blood Adv 2:1957-1968
Liu, Chen; Kellems, Rodney E; Xia, Yang (2017) Inflammation, Autoimmunity, and Hypertension: The Essential Role of Tissue Transglutaminase. Am J Hypertens 30:756-764

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