Diabetic retinopathy is a sight threatening disease without effective therapeutic options. The diabetic metabolic insult leading to retinal vascular degeneration is proposed to involve the initial endothelial cell damage due to low-grade chronic inflammation;that is then inadequately repaired due to compromised availability and functionality of bone marrow derived endothelial progenitor cells (EPCs). We have previously demonstrated that bone marrow pathology with EPC dysfunction precedes and is necessary for retinal vascular degeneration in diabetes. We propose that a molecular metabolic link connecting both the initial inflammation in the retina and the dysfunctional EPCs involves downregulation of ?-3 polyunsaturated fatty acids (PUFA) with concomitant activation of the central enzyme of sphingolipid signaling, acid sphingomyelinase (ASM). Our recent study demonstrated a significant decrease in total 3-PUFAs, especially DHA, that was tightly coupled with increased inflammatory changes in the diabetic retina. DHA supplementation corrected the diabetes induced decrease in migration and proliferation in EPCs, and prevented diabetes induced retinal inflammation and retinal vessel loss. These findings fit with other studies showing potent anti-inflammatory properties of omega-3 PUFAs. Dysregulation of sphingolipid metabolism is believed to play a major role in insulin resistance, obesity and inflammation. We identified activation of ASM, the enzyme converting sphingomyelin into pro- inflammatory and pro-apoptotic ceramide, as a key element activated by diabetes in both EPCs and retinal vasculature. We found that DHA supplementation reversed increases in ASM activity in diabetic EPCs and retinal endothelial cells. ASM-/- animals were protected from vascular degeneration in retinopathy models. Based on these data we hypothesize that DHA supplementation improves the outcomes of diabetic retinopathy by: 1) preventing endothelial cell activation and subsequent damage in the retina;and 2) through improving retinal vascular repair by correcting the function of bone marrow derived EPCs. We propose that the beneficial effects of DHA are due, at least in part, to inhibition of ASM activity in retinal endothelial cells and bone marrow derived EPCs. This hypothesis will be tested in two Specific Aims.
Aim 1 will address retinal endothelial specific effects and Aim 2 will address EPC specific effects of ASM in diabetes. The proposed studies will assess the potential of ASM as a target for the treatment of diabetic retinopathy. Moreover, we will identify the extend of therapeutic potential that can be achieve by retinal-specific and bone-marrow specific inhibition of ASM to determine the best therapeutic strategies.

Public Health Relevance

Dysregulation of sphingolipid metabolism is becoming recognized as an important partof diabetic dyslipidemia playing a major role in insulin resistance; obesity andinflammation; and the role of sphingolipid metabolism in the retina is beginning toemerge. Our preliminary studies demonstrate that diets supplemented with 3 PUFA-rich effectively corrected retinal pathology in both type 1 and type 2 diabetes animalmodels through; at least in part; inhibition of acid sphingomyelinase; the major enzymeat the top of sphingolipid pathway. This proposal will address the role of acidsphingomyelinase activation in the pathogenesis of diabetic retinopathy and will providenovel therapeutic targets for this sight threatening disease.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY016077-07
Application #
8585067
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Shen, Grace L
Project Start
2004-12-01
Project End
2014-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
7
Fiscal Year
2014
Total Cost
$334,667
Indirect Cost
$95,947
Name
Michigan State University
Department
Physiology
Type
Schools of Osteopathic Medicine
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
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Wang, Qi; Bozack, Svetlana N; Yan, Yuanqing et al. (2014) Regulation of retinal inflammation by rhythmic expression of MiR-146a in diabetic retina. Invest Ophthalmol Vis Sci 55:3986-94
Bennett, Lea D; Brush, Richard S; Chan, Michael et al. (2014) Effect of reduced retinal VLC-PUFA on rod and cone photoreceptors. Invest Ophthalmol Vis Sci 55:3150-7
Tikhonenko, Maria; Lydic, Todd A; Opreanu, Madalina et al. (2013) N-3 polyunsaturated Fatty acids prevent diabetic retinopathy by inhibition of retinal vascular damage and enhanced endothelial progenitor cell reparative function. PLoS One 8:e55177
Kielczewski, Jennifer L; Li Calzi, Sergio; Shaw, Lynn C et al. (2011) Free insulin-like growth factor binding protein-3 (IGFBP-3) reduces retinal vascular permeability in association with a reduction of acid sphingomyelinase (ASMase). Invest Ophthalmol Vis Sci 52:8278-86
Opreanu, Madalina; Tikhonenko, Maria; Bozack, Svetlana et al. (2011) The unconventional role of acid sphingomyelinase in regulation of retinal microangiopathy in diabetic human and animal models. Diabetes 60:2370-8
Tikhonenko, Maria; Lydic, Todd A; Wang, Yun et al. (2010) Remodeling of retinal Fatty acids in an animal model of diabetes: a decrease in long-chain polyunsaturated fatty acids is associated with a decrease in fatty acid elongases Elovl2 and Elovl4. Diabetes 59:219-27
Opreanu, Madalina; Lydic, Todd A; Reid, Gavin E et al. (2010) Inhibition of cytokine signaling in human retinal endothelial cells through downregulation of sphingomyelinases by docosahexaenoic acid. Invest Ophthalmol Vis Sci 51:3253-63
Busik, Julia V; Tikhonenko, Maria; Bhatwadekar, Ashay et al. (2009) Diabetic retinopathy is associated with bone marrow neuropathy and a depressed peripheral clock. J Exp Med 206:2897-906
Lydic, Todd A; Renis, Rebecca; Busik, Julia V et al. (2009) Analysis of Retina and Erythrocyte Glycerophospholipid Alterations in a Rat Model of Type 1 Diabetes. JALA Charlottesv Va 14:383-399

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