Significant visual loss may result from retinal ischemia in retinal arterial or venous occlusion, glaucoma, atherosclerosis, or in systemic disorders such as diabetes mellitus. The pathogenesis involves changes in cellular biochemistry and energy level, blood flow, and gene expression. During the past 11 years of this project, we documented extensive biochemical, functional, structural, and hemo-'dynamic evidence for the complex, but major involvement of the purine nucleoside adenosine in retinal ischemia-reperfusion injury. More recently, we also discovered the closely related and dramatic finding of complete functional and histological protection from ischemic damage in the in vivo retina conferred by a brief period of non damaging ischemia, i.e., ischemic preconditioning (IPC). Other significant accompanying protective mechanisms of IPC include the attenuation of hypoperfusion, protein phosphorylation, and apoptosis. We demonstrated that adeno-'sine is a trigger for IPC, and we began to uncover the roles of downstream signal transduction factors, including mitochondrial KATP channels, PKC, mitogen-activated protein kinase p38, nitric oxide, and reactive oxygen species, in this neuroprotection. These exciting results extend our earlier findings of the remarkable functional and histological protection from ischemic damage afforded by IPC, indicating that IPC has a profound influence upon cell signaling and survival. Examination of the mechanisms responsible for IPC in our established retinal ischemia model provides a unique and innovative window into the retina's endogenous ability to counter ischemic injury.
The first aim will characterize the signaling pathwaysfor IPC involving mitochondrial KATP channels and the associated signal transduction factors.
The second aim will characterize the involvement of NOS and PKC subtypes as essential signaling intermediaries in IPC.
The third aim will examine the mechanisms of the paradoxical effect whereby transient MAPK p38 expression protects the retina, while its blockade prior to ischemia protects against ischemic damage. Our experiments will definitively examine major mechanisms of IPC and should bring us closer to understanding molecular events underlying this robust, intriguing, and clinically relevant neuroprotection.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY010343-16
Application #
7764756
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Neuhold, Lisa
Project Start
1994-01-01
Project End
2011-12-31
Budget Start
2010-03-01
Budget End
2011-12-31
Support Year
16
Fiscal Year
2010
Total Cost
$368,896
Indirect Cost
Name
University of Chicago
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Calway, Tyler; Rubin, Daniel S; Moss, Heather E et al. (2017) Perioperative Retinal Artery Occlusion: Risk Factors in Cardiac Surgery from the United States National Inpatient Sample 1998-2013. Ophthalmology 124:189-196
Rubin, Daniel S; Matsumoto, Monica M; Moss, Heather E et al. (2017) Ischemic Optic Neuropathy in Cardiac Surgery: Incidence and Risk Factors in the United States from the National Inpatient Sample 1998 to 2013. Anesthesiology 126:810-821
Calway, Tyler; Rubin, Daniel S; Moss, Heather E et al. (2017) Perioperative Retinal Artery Occlusion: Incidence and Risk Factors in Spinal Fusion Surgery From the US National Inpatient Sample 1998-2013. J Neuroophthalmol :
Mathew, Biji; Poston, Jacqueline N; Dreixler, John C et al. (2017) Bone-marrow mesenchymal stem-cell administration significantly improves outcome after retinal ischemia in rats. Graefes Arch Clin Exp Ophthalmol 255:1581-1592
Roth, Steven; Dreixler, John C; Mathew, Biji et al. (2016) Hypoxic-Preconditioned Bone Marrow Stem Cell Medium Significantly Improves Outcome After Retinal Ischemia in Rats. Invest Ophthalmol Vis Sci 57:3522-32
Rubin, Daniel S; Parakati, Isaac; Lee, Lorri A et al. (2016) Perioperative Visual Loss in Spine Fusion Surgery: Ischemic Optic Neuropathy in the United States from 1998 to 2012 in the Nationwide Inpatient Sample. Anesthesiology 125:457-64
Roth, Steven (2015) Inhaled Anesthesia, Apoptosis, and the Developing Retina: A Window into the Brain? Anesth Analg 121:1117-8
Sampat, Ajay; Parakati, Isaac; Kunnavakkam, Rangesh et al. (2015) Corneal abrasion in hysterectomy and prostatectomy: role of laparoscopic and robotic assistance. Anesthesiology 122:994-1001
Dreixler, John C; Poston, Jacqueline N; Balyasnikova, Irina et al. (2014) Delayed administration of bone marrow mesenchymal stem cell conditioned medium significantly improves outcome after retinal ischemia in rats. Invest Ophthalmol Vis Sci 55:3785-96
Dreixler, John C; Poston, Jacqueline N; Shaikh, Afzhal R et al. (2011) Delayed post-ischemic conditioning significantly improves the outcome after retinal ischemia. Exp Eye Res 92:521-7

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