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.
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.
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