Why do neurons in the mature central nervous system (CNS) die after injury? White matter ischemia (stroke) leads to axon injury and then in most cases to death of CNS neurons. Thus, for example, ischemic optic neuropathy leads to retinal ganglion cell (RGC, a type of CNS neuron) dysfunction and death, and permanent loss of vision. Although many of the downstream molecular pathways of cell death and apoptosis are under intensive study, the upstream signals that regulate survival and axon regeneration after axon injury are not known. Recent evidence suggests that RGCs die after axon injury for two reasons: they are cut off from target-derived trophic signals, and they become less responsive to such signals. Trophic responsiveness, survival and regeneration can be enhanced by elevating cyclic AMP (cAMP), but the signal transduction pathways remain largely unstudied. Here we will use the rodent retina and optic nerve as a model system for CNS neurons and their axonal, white matter pathways, respectively, and test the hypothesis that compartmentalized signaling on a family of scaffold proteins called AKAPs regulate survival and regeneration signaling in a novel model of white matter stroke in the optic nerve. In three Specific Aims, we will (1) identify the specific adenylyl cyclases responsible for cAMP signaling in primary neurons~ (2) identify the specific AKAP-related signaling pathways potentiated by cAMP and contributing to neuronal survival and regeneration~ and (3) determine whether manipulating AKAP-mediated signalosomes in vivo regulates neuronal survival and regeneration in vivo after ischemic axon injury. We hope through these experiments to determine the molecular basis for the failure of RGC survival after ischemic axon injury, and ultimately to develop new treatments to maintain CNS neuronal survival after white matter ischemia.

Public Health Relevance

Stroke leads to injury and then in most cases to death of central nervous system neurons. Similarly, ischemic optic neuropathy leads to retinal ganglion cell (RGC, a type of CNS neuron) axon injury, followed by RGC dysfunction and death, and permanent loss of vision. Here we will study the signaling of neuronal survival and regeneration in a new model of white matter ischemic axon injury, using the optic nerve as a relevant model. Our hope is to understand why RGCs fail to survive after ischemic optic neuropathy, and to develop new treatments to maintain CNS neuronal survival after white matter ischemia.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
7R01EY022129-06
Application #
9121089
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Chin, Hemin R
Project Start
2015-09-01
Project End
2015-11-30
Budget Start
2015-09-01
Budget End
2015-11-30
Support Year
6
Fiscal Year
2015
Total Cost
$508,687
Indirect Cost
$89,157
Name
Stanford University
Department
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94304
Galvao, Joana; Iwao, Keiichiro; Apara, Akintomide et al. (2018) The Krüppel-Like Factor Gene Target Dusp14 Regulates Axon Growth and Regeneration. Invest Ophthalmol Vis Sci 59:2736-2747
Shaw, Peter X; Sang, Alan; Wang, Yan et al. (2017) Topical administration of a Rock/Net inhibitor promotes retinal ganglion cell survival and axon regeneration after optic nerve injury. Exp Eye Res 158:33-42
Apara, Akintomide; Galvao, Joana; Wang, Yan et al. (2017) KLF9 and JNK3 Interact to Suppress Axon Regeneration in the Adult CNS. J Neurosci 37:9632-9644
Cameron, Evan G; Kapiloff, Michael S (2017) Intracellular compartmentation of cAMP promotes neuroprotection and regeneration of CNS neurons. Neural Regen Res 12:201-202
Goldberg, Jeffrey L; Guido, William; Agi Workshop Participants (2016) Report on the National Eye Institute Audacious Goals Initiative: Regenerating the Optic Nerve. Invest Ophthalmol Vis Sci 57:1271-5
Shaw, Peter X; Fang, Jiahua; Sang, Alan et al. (2016) Soluble Adenylyl Cyclase Is Required for Retinal Ganglion Cell and Photoreceptor Differentiation. Invest Ophthalmol Vis Sci 57:5083-5092
Wang, Yan; Brown, Dale P; Watson, Brant D et al. (2015) Rat Model of Photochemically-Induced Posterior Ischemic Optic Neuropathy. J Vis Exp :
Wang, Yan; Cameron, Evan G; Li, Jinliang et al. (2015) Muscle A-Kinase Anchoring Protein-? is an Injury-Specific Signaling Scaffold Required for Neurotrophic- and Cyclic Adenosine Monophosphate-Mediated Survival. EBioMedicine 2:1880-7
Stiles, Travis L; Kapiloff, Michael S; Goldberg, Jeffrey L (2014) The role of soluble adenylyl cyclase in neurite outgrowth. Biochim Biophys Acta 1842:2561-8
Wang, Yan; Brown Jr, Dale P; Duan, Yuanli et al. (2013) A novel rodent model of posterior ischemic optic neuropathy. JAMA Ophthalmol 131:194-204

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