The term "cAMP" usually refers to the second messenger 3',5'-cyclic adenosine monophosphate. We serendipitously discovered that organ systems can produce (from mRNA degradation) and export to the extracellular compartment a positional isomer of 3',5'-cAMP, namely 2',3'-cAMP. We showed that organ systems convert extracellular 2',3'-cAMP to 2'-AMP + 3'-AMP and can metabolize 2'-AMP and 3'-AMP to adenosine. We refer to this pathway as the "2',3'-cAMP-adenosine pathway." We also showed that extracellular 2',3'-cAMP increases greatly post-traumatic brain injury (TBI) in brain in rodents and humans;and that when the pathway is impaired, TBI outcomes worsen in rodents. Intracellular 2',3'-cAMP opens mitochondrial permeability transition pores while extracellular adenosine is neuroprotective. Thus the "2',3'- cAMP-adenosine pathway" may be important in TBI because it eliminates an intracellular neurotoxin (export of 2',3'-cAMP) and generates an extracellular neuroprotectant (conversion of 2',3'-cAMP to adenosine). We also identified the enigmatic myelin protein 2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNPase) to be the major enzyme that metabolizes extracellular 2',3'-cAMP to 2'-AMP (a key step toward conversion into adenosine). KO mice lacking CNPase produce less extracellular adenosine post-TBI, are more susceptible to injury and develop axonal degeneration with age despite no gross myelin abnormalities. Hypothesis: the "2',3'-cAMP- adenosine pathway" is an endogenous cytoprotective mechanism after TBI. We will elucidate which CNS cell types produce 2',3'-cAMP, what kinds of injury trigger 2',3'-cAMP production, how 2',3'-cAMP is transported out of cells, how downstream AMPs are converted to adenosine, and if manipulating the 2',3'-cAMP-adenosine pathway alters secondary damage.
Specific Aim 1 : To determine which CNS cell types produce 2',3'-cAMP after injury. Because in vivo TBI increases extracellular 2',3'-cAMP, it is important to determine which CNS cells produce 2',3'-cAMP and whether the effect is injury-type dependent.
Aim 1 will determine if metabolic stress, hypoxia or mechanical injury enhances 2',3'-cAMP production by astrocytes, microglia, neurons or oligodendrocytes.
Specific Aim 2 : To determine whether Multidrug Resistance Protein 4 (MRP4) mediates egress of 2',3'-cAMP. Because 2',3'-cAMP is an intracellular toxin, it is critical to elucidate how 2',3'-cAMP is extrude from CNS cells.
Aim 2 will test the hypothesis that MRP4 exports 2',3'-cAMP.
Specific Aim 3 : To determine if Tissue Alkaline Phosphatase (TAP) participates in the extracellular metabolism of 2'-AMP and 3'- AMP (downstream metabolites of 2',3'-cAMP) to adenosine. Because extracellular adenosine is neuroprotective it is essential to understand how extracellular 2'-AMP and 3'-AMP are converted to extracellular adenosine.
Specific Aim 4 : To test the hypothesis that the 2',3'-cAMP-adenosine pathway is an endogenous protective mechanism post-TBI.
Aim 4 will further test the hypothesis that the 2',3'-cAMP- adenosine pathway is cytoprotective by determining the effect of inhibiting or augmenting it on TBI outcomes.

Public Health Relevance

The term cAMP usually refers to the second messenger 3',5'-cyclic adenosine monophosphate. We serendipitously discovered that brain can produce (from mRNA degradation) and export to the extracellular compartment a positional isomer of 3',5'-cAMP, namely 2',3'-cAMP. 2',3'-cAMP is neurotoxic but its metabolite adenosine is neuroprotective. This new 2',3'-cAMP-adenosine pathway thus has promise as a target for development of novel therapies for brain injury. In this proposal we will evaluate approaches to manipulate this novel pathway with the goal of developing a novel therapy for the important public health problem of traumatic brain injury.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
1R01NS087978-01
Application #
8734766
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Bellgowan, Patrick S F
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Rigassi, Lisa; Barchiesi Bozzolo, Federica; Lucchinetti, Eliana et al. (2015) 2-Methoxyestradiol blocks the RhoA/ROCK1 pathway in human aortic smooth muscle cells. Am J Physiol Endocrinol Metab 309:E995-1007
Newell, Elizabeth A; Exo, Jennifer L; Verrier, Jonathan D et al. (2015) 2',3'-cAMP, 3'-AMP, 2'-AMP and adenosine inhibit TNF-α and CXCL10 production from activated primary murine microglia via A2A receptors. Brain Res 1594:27-35
Jackson, Travis C; Du, Lina; Janesko-Feldman, Keri et al. (2015) The nuclear splicing factor RNA binding motif 5 promotes caspase activation in human neuronal cells, and increases after traumatic brain injury in mice. J Cereb Blood Flow Metab 35:655-66
Dubey, Raghvendra K; Fingerle, Jürgen; Gillespie, Delbert G et al. (2015) Adenosine Attenuates Human Coronary Artery Smooth Muscle Cell Proliferation by Inhibiting Multiple Signaling Pathways That Converge on Cyclin D. Hypertension 66:1207-19
Kochanek, Patrick M; Jackson, Travis C (2015) It might be time to let cooler heads prevail after mild traumatic brain injury or concussion. Exp Neurol 267:13-7
Diamond, Matthew L; Ritter, Anne C; Jackson, Edwin K et al. (2015) Genetic variation in the adenosine regulatory cycle is associated with posttraumatic epilepsy development. Epilepsia 56:1198-206

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