The contribution of circulating hematopoietic stem cells (HSCs) to vascular dysfunction remains controversial. Our data, however, support a critical role for these cells in proper retinal repair, their dependence on hypoxia regulated factors such as stromal derived factor (SDF-1) and VEGF for their recruitment to ischemic sites, and their marked dysfunction in diabetes. We propose to test the following hypothesis: In the nondiabetic state, CD34+ cells are the primary cells responding to any ischemia or injury in the retina and engage in effective revascularization and repair within the retina. Diabetes reduces the reparative potential of CD34+ cells favoring the participation of inflammatory CD14+ cells to the repair process. However, CD14+ cells form dysfunctional vessels resulting in persistent retinal ischemia and subsequent development of preretinal neovascularization. Thus, we suggest that in diabetes, the functional balance is upset by promotion of activity of one of these phenotypes (CD14+ cells) over the other (CD34+ cells). To test the above hypotheses, we will use a unique combination of experimental approaches to integrate findings on in vitro characterization of human CD34+ and CD14+ cells modulated by hypoxia with in vivo studies using rodent models of retinal ischemia and diabetes. We propose the following Specific Aims 1) To examine the effect of hypoxia-regulated factors, VEGF, SDF-1 and IGF binding protein-3, on CD34+ and CD14+ cell attachment to, differentiation on, and invasion into advance glycation endproduct(AGE)- modified matrix proteins. 2) In CD34+ and CD14+ cells, to compare the effect of hypoxia on a) expression of VEGF receptors, SDF-1 receptor, CXCR4 and IGF-1 receptor, b) migration and c) formation of capillary tubes in the presence retinal endothelial cells using a co-culture model. 3) To examine the recruitment and integration of nondiabetic and diabetic EPCs in vivo using two models of retinal ischemia in SCID mice and examine the potential of EPCs of diabetic and non-diabetic origin to repair acellular capillaries in diabetic mice and examine the effects of hypoxia pre-conditioning on these same cells. These studies will allow us to carefully examine the contribution of these two key endothelial precursor cell populations to the proper vs. aberrant repair of the retinal vasculature.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY007739-20
Application #
7751253
Study Section
Special Emphasis Panel (ZRG1-CB-G (90))
Program Officer
Shen, Grace L
Project Start
1989-08-01
Project End
2011-12-31
Budget Start
2010-01-01
Budget End
2010-12-31
Support Year
20
Fiscal Year
2010
Total Cost
$360,112
Indirect Cost
Name
University of Florida
Department
Pharmacology
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Yan, Yuanqing; Gao, Ruli; Trinh, Thao L P et al. (2017) Immunodeficiency in Pancreatic Adenocarcinoma with Diabetes Revealed by Comparative Genomics. Clin Cancer Res 23:6363-6373
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
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
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
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
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
Dominguez 2nd, James M; Hu, Ping; Caballero, Sergio et al. (2016) Adeno-Associated Virus Overexpression of Angiotensin-Converting Enzyme-2 Reverses Diabetic Retinopathy in Type 1 Diabetes in Mice. Am J Pathol 186:1688-700
Beli, Eleni; Dominguez 2nd, James M; Hu, Ping et al. (2016) CX3CR1 deficiency accelerates the development of retinopathy in a rodent model of type 1 diabetes. J Mol Med (Berl) 94:1255-1265

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