The fundamental gap in understanding endogenous neuroprotection evoked by ischemic tolerance impedes identification of therapeutic targets for retinal ischemia, a major cause of visual loss. Involvement of inflammation, glial activation, oxidative stress, and neurodegeneration in chronic retinal ischemic diseases such as diabetic retinopathy, suggests a primary role for neuroprotection. The long-term goal is to decipher the mechanisms of endogenous ischemic tolerance, as an innovative modulator of ischemic injury. The overall objective is to understand the activation, control, and downstream mechanisms of two key proteins, Akt and p38, in ischemic tolerance. The central hypothesis is that their activation, individually or together, drives retinal endogenous tolerance. Underlying the hypothesis is the applicant's results in a rat model wherein p38 evoked, while blocking specific Akt subtypes, attenuated ischemic tolerance. Akt or p38 knockdown inhibited the conceptually-related post-ischemic conditioning (transient ischemia after the damaging ischemia). Rationale for the proposal is that, after understanding these signaling mechanisms, the pathways can be precisely tuned, potentially translating into effective treatment for the >10 million/year at risk for retinal ischemia. The central hypothesis will be tested in three specific aims: 1) Identify p38 neuroprotective signaling, 2) Identify Akt neuroprotective signaling, 3) Determine mechanisms of delayed post-ischemic conditioning related to p38 and Akt.
In Aim 1, an established RNA interference approach (siRNA) will examine p38's control and downstream mechanisms in ischemic tolerance.
In Aim 2, siRNA will block Akt, and a novel Akt phosphomimetic viral vector whose efficacy is supported by preliminary data, will over express Akt subtypes. Measuring substrates of Akt subtypes, and pathway cross-talk will illuminate the mechanisms of neuroprotection.
In Aim 3, using the PI's delayed retinal ischemic post-conditioning model, examination of Akt, p38, and downstream mediators will elucidate the mechanisms of restoration of post-ischemic neuronal function. Experimental outcomes will be measured in Aims 1-3 by modern, validated molecular and physiological approaches that are well established in the applicant's lab. Innovatively exploiting endogenous neuroprotection by providing ischemic tolerance will yield novel targets to treat ischemic disease by engaging cell survival mechanisms. The proposed research is significant because it is expected to vertically advance and expand understanding of how the retina's endogenous cellular machinery can be harnessed to prevent or treat ischemia, while increasing understanding of cell survival signaling in vivo. Ultimately, this knowledge has potential to transform treatment of retinal ischemia by identifying novel, specific molecular interventional targets that will help to decrease the growing problem of visual loss and disability from ischemic disease in the retina.

Public Health Relevance

Retinal ischemia is a common cause of visual impairment and blindness. The proposed research is relevant to public health because identifying the mechanisms of endogenous retinal ischemic tolerance mediated by protein kinas-related signaling is ultimately expected to stimulate development of safe, effective, and innovative treatment or prevention strategies for people at risk for ischemic diseases, as well as enhanced understanding of cellular signaling in vivo. Thus the proposed research is relevant to the part of NIH's mission that pertains to developing fundamental knowledge that will help to reduce the burdens of human disability.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY010343-17A1
Application #
8237595
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Shen, Grace L
Project Start
1994-01-01
Project End
2014-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
17
Fiscal Year
2012
Total Cost
$390,000
Indirect Cost
$140,000
Name
University of Chicago
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Kadzielawa, Konrad; Mathew, Biji; Stelman, Clara R et al. (2018) Gene expression in retinal ischemic post-conditioning. Graefes Arch Clin Exp Ophthalmol 256:935-949
Calway, Tyler; Rubin, Daniel S; Moss, Heather E et al. (2018) Perioperative Retinal Artery Occlusion: Incidence and Risk Factors in Spinal Fusion Surgery From the US National Inpatient Sample 1998-2013. J Neuroophthalmol 38:36-41
Roth, Steven; Moss, Heather E (2018) Update on Perioperative Ischemic Optic Neuropathy Associated With Non-ophthalmic Surgery. Front Neurol 9:557
Roth, Steven; Dreixler, John; Newman, Nancy J (2018) Haemodilution and head-down tilting induce functional injury in the rat optic nerve: A model for peri-operative ischemic optic neuropathy. Eur J Anaesthesiol 35:840-847
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
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: Risk Factors in Cardiac Surgery from the United States National Inpatient Sample 1998-2013. Ophthalmology 124:189-196
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

Showing the most recent 10 out of 51 publications