Diabetic retinopathy (DR) is a sight threatening disease with few therapeutic options. Low-grade chronic inflammation in the retina [1-8] and inadequate vascular repair due to compromised function of the bone marrow (BM)-derived circulating angiogenic cells (CACs) [9-12] contribute to progression of retinal vascular pathology. A number of hyperglycemia- and dyslipidemia- activated pathways promoting the increase of pro-inflammatory cytokines, pro-inflammatory lipids and pro-angiogenic factors leading to retinal endothelial cell and CAC dysfunction have been identified [2-4, 6, 9, 10, 13-25]. Dysregulation of these pathways is hypothesized to involve microRNAs (miRNAs). These small non-coding RNAs anneal imperfectly to target genes and simultaneously control translation and transcription [26]. Several miRNA classes have been shown to contribute to diabetes and diabetic complications [27, 28], including diabetic retinopathy [29]. Studies during the previous funding period identified miR-15a as a key regulator of both pro-inflammatory and pro-angiogenic pathways. miR-15a accomplishes these tasks through direct binding and inhibition of the central enzyme in the sphingolipid pathway, acid sphingomyelinase (ASM), and inhibition of VEGF-A. Based on these data, we hypothesize that miRNAs represent therapeutic targets for prevention and treatment of DR by simultaneously regulating pro-inflammatory and pro-angiogenic pathways in the retina and CACs. We will address the role of miR-15a in DR with the following Specific Aims.
Specific aim 1 : To test the hypothesis that the decrease in miR-15a observed in diabetes contributes to increased ASM activity and VEGF-A production leading to pro- inflammatory changes, increased permeability and endothelial dysfunction in the retina.
Specific aim 2 : To test the hypothesis that decrease in miR-15a in diabetes leads to ASM activation and ceramide production resulting in decreased membrane fluidity of bone marrow-derived CACs. Decreased membrane fluidity results in entrapment of progenitor cell in the bone marrow and reduced repair function due to impaired migration and extravasation capacity. Manipulation of miR-15a to simultaneously control sphingolipid metabolism and pro-angiogenic pathways through direct regulation of ASM and VEGF-A production in the diabetic retina and BM should provide a unique and effective combination therapy approach that will add to the pharmacological armamentarium of drug therapies for diabetic retinopathy.

Public Health Relevance

Diabetic retinopathy is a sight threatening disease without effective therapeutic options. We identified activation of ASM, the enzyme converting sphingomyelin into ceramide, as a key element affecting both diabetes-induced vascular damage and bone marrow derived circulating angiogenic cell mediated repair of retinal vasculature. This proposal will test the hypothesis that miRNAs may serve as therapeutic targets for the prevention and treatment of DR through their ability to simultaneously regulate ASM and VEGF production in both the retina and circulating angiogenic cells.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY016077-10
Application #
9398123
Study Section
Diseases and Pathophysiology of the Visual System Study Section (DPVS)
Program Officer
Shen, Grace L
Project Start
2004-12-01
Project End
2020-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
10
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Michigan State University
Department
Physiology
Type
Schools of Osteopathic Medicine
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
Kady, Nermin; Yan, Yuanqing; Salazar, Tatiana et al. (2017) Increase in acid sphingomyelinase level in human retinal endothelial cells and CD34+ circulating angiogenic cells isolated from diabetic individuals is associated with dysfunctional retinal vasculature and vascular repair process in diabetes. J Clin Lipidol 11:694-703
Blanchard, Gary J; Busik, Julia V (2017) Interplay between Endothelial Cell Cytoskeletal Rigidity and Plasma Membrane Fluidity. Biophys J 112:831-833
Hammer, Sandra S; Beli, Eleni; Kady, Nermin et al. (2017) The Mechanism of Diabetic Retinopathy Pathogenesis Unifying Key Lipid Regulators, Sirtuin 1 and Liver X Receptor. EBioMedicine 22:181-190
Hammer, Sandra S; Busik, Julia V (2017) The role of dyslipidemia in diabetic retinopathy. Vision Res 139:228-236
Mize, Hannah E; Blanchard, G J (2016) Interface-mediation of lipid bilayer organization and dynamics. Phys Chem Chem Phys 18:16977-85
Chakravarthy, Harshini; Navitskaya, Svetlana; O'Reilly, Sandra et al. (2016) Role of Acid Sphingomyelinase in Shifting the Balance Between Proinflammatory and Reparative Bone Marrow Cells in Diabetic Retinopathy. Stem Cells 34:972-83
Wang, Qi; Navitskaya, Svetlana; Chakravarthy, Harshini et al. (2016) Dual Anti-Inflammatory and Anti-Angiogenic Action of miR-15a in Diabetic Retinopathy. EBioMedicine 11:138-150
Chakravarthy, Harshini; Beli, Eleni; Navitskaya, Svetlana et al. (2016) Imbalances in Mobilization and Activation of Pro-Inflammatory and Vascular Reparative Bone Marrow-Derived Cells in Diabetic Retinopathy. PLoS One 11:e0146829
Busik, Julia V; Grant, Maria B (2015) Wnting out ocular neovascularization: using nanoparticle delivery of very-low density lipoprotein receptor extracellular domain as Wnt pathway inhibitor in the retina. Arterioscler Thromb Vasc Biol 35:1046-7
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

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