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)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
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
2014-07-01
Project End
2019-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
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
Jackson, Edwin K; Menshikova, Elizabeth V; Mi, Zaichuan et al. (2016) Renal 2',3'-Cyclic Nucleotide 3'-Phosphodiesterase Is an Important Determinant of AKI Severity after Ischemia-Reperfusion. J Am Soc Nephrol 27:2069-81
Tamburro, Robert F; Jenkins, Tammara L; Kochanek, Patrick M (2016) Strategic Planning for Research in Pediatric Critical Care. Pediatr Crit Care Med 17:e539-e542
Schaufelberger, Sara A; Rosselli, Marinella; Barchiesi, Federica et al. (2016) 2-Methoxyestradiol, an endogenous 17β-estradiol metabolite, inhibits microglial proliferation and activation via an estrogen receptor-independent mechanism. Am J Physiol Endocrinol Metab 310:E313-22
Kochanek, Patrick M; Jackson, Travis C; Ferguson, Nikki Miller et al. (2015) Emerging therapies in traumatic brain injury. Semin Neurol 35:83-100
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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