Diabetic retinopathy, the leading cause of new blindness in individuals between the ages of 20-74 (1), is a disease process for which the pathological (anatomic) stages are well described. The underlying mechanisms, however, remain ill-defined or unknown. The plasminogen activator system consists of the proteases, tissue type-plasminogen activator and urokinase, and their natural inhibitors, plasminogen activator InhIbitor-1 (PAI-1) and PAI-2. The plasminogen activator system controls fibrinolysis and regulates extracellular matrix proteolysis. Disturbances in this system, in particular the overexpression of PAI by endothelial cells, in response to peptide hormones, growth factors, and cytokines, may be relevant to the pathogenesis of diabetic retinopathy.
Aim 1. involves testing the hypothesis that elevated PAI levels result in the basement membrane thickening seen in diabetic retinal vessels. This will be tested by: A. Determining whether PAIs are expressed in greater quantities in the retinal capillaries of diabetics utilizing immunocytochemical studies. B. Assessing whether the exogenous administration of a synthetic PAI results in basement membrane thickening in the retinal vasculature. We will use direct intravitreal administration of synthetic PAIs followed by morphological studies. C. Determining whether overexpression of PAI-1 in the retinal vasculature results in similar retinal pathology to that observed in the diabetic. We will use morphometric analysis of capillaries in ocular tissue from transgenic mice overexpressing PAI-1 Aim 2. involves testing the hypothesis that the absence of PAI-1 makes the retinal vasculature resistant to developing diabetes induced changes. Utilizing PAI-1 deficient mice made diabetic by administration of streptozotocin.
Aim 3. involves testing the hypothesis that IGF-l, regulated by the IGF binding proteins, and selected cytokines act as modulators of PAI-1 expression and that the diabetic state affects IGF-l regulation within the retina. These studies will utilize human retinal endothelial cells and donor human ocular tissue. Through the studies proposed in this application an understanding of the molecular mechanisms of PAI regulation by the retinal vasculature will be gained. The studies are critical to determining appropriate therapeutic interventions, including the use of agents such as growth factor inhibitors, anti-inflammatory agents, and agents such as metformin, that decrease PAI levels, in the management of diabetic patients before the development of clinically apparent background retinopathy.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY007739-09
Application #
2701371
Study Section
Visual Sciences C Study Section (VISC)
Program Officer
Linder, Barbara
Project Start
1989-08-01
Project End
1999-04-30
Budget Start
1998-05-01
Budget End
1999-04-30
Support Year
9
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Florida
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073130411
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Shaw, Lynn Calvin; Li Calzi, Sergio; Li, Nan et al. (2018) Enteral Arg-Gln Dipeptide Administration Increases Retinal Docosahexaenoic Acid and Neuroprotectin D1 in a Murine Model of Retinopathy of Prematurity. Invest Ophthalmol Vis Sci 59:858-869
Bhatwadekar, Ashay D; Beli, Eleni; Diao, Yanpeng et al. (2017) Conditional Deletion of Bmal1 Accentuates Microvascular and Macrovascular Injury. Am J Pathol 187:1426-1435
Caballero, Sergio; Kent, David L; Sengupta, Nilanjana et al. (2017) Bone Marrow-Derived Cell Recruitment to the Neurosensory Retina and Retinal Pigment Epithelial Cell Layer Following Subthreshold Retinal Phototherapy. Invest Ophthalmol Vis Sci 58:5164-5176
Bhatwadekar, Ashay D; Duan, Yaqian; Korah, Maria et al. (2017) Hematopoietic stem/progenitor involvement in retinal microvascular repair during diabetes: Implications for bone marrow rejuvenation. Vision Res 139:211-220
Basavarajappa, Halesha D; Sulaiman, Rania S; Qi, Xiaoping et al. (2017) Ferrochelatase is a therapeutic target for ocular neovascularization. EMBO Mol Med 9:786-801
Salazar, Tatiana E; Richardson, Matthew R; Beli, Eleni et al. (2017) Electroacupuncture Promotes Central Nervous System-Dependent Release of Mesenchymal Stem Cells. Stem Cells 35:1303-1315
Hu, Ping; Hunt, Nicholas H; Arfuso, Frank et al. (2017) Increased Indoleamine 2,3-Dioxygenase and Quinolinic Acid Expression in Microglia and Müller Cells of Diabetic Human and Rodent Retina. Invest Ophthalmol Vis Sci 58:5043-5055
Song, Chunjuan; Mitter, Sayak K; Qi, Xiaoping et al. (2017) Oxidative stress-mediated NF?B phosphorylation upregulates p62/SQSTM1 and promotes retinal pigmented epithelial cell survival through increased autophagy. PLoS One 12:e0171940
Abcouwer, Steven F (2017) Müller Cell-Microglia Cross Talk Drives Neuroinflammation in Diabetic Retinopathy. Diabetes 66:261-263
Li, Wennan; Chen, Xingjuan; Riley, Ashley M et al. (2017) Long-term spironolactone treatment reduces coronary TRPC expression, vasoconstriction, and atherosclerosis in metabolic syndrome pigs. Basic Res Cardiol 112:54

Showing the most recent 10 out of 93 publications