Diabetes induces a systemic low-grade chronic inflammatory response. Leukocytes are a key mediator of inflammation throughout the body. In the setting of diabetes leukocyte aggregation and adhesion are increased at sites of retinal microvascular dysfunction. Worsening degrees of diabetic retinopathy correlate with increasing amounts of leukocyte endothelial adhesion. The objective of this proposal is to assess whether differences in leukocyte endothelial adhesion between individuals with diabetes contribute to diabetic retinopathy outcomes. The study will determine whether leukocyte endothelial adhesion represents an independent risk factor for diabetic retinopathy. While it is recognized that leukocyte mediated inflammation plays an important role in the pathogenesis of diabetic retinopathy, its relevance and clinical importance are presently unknown. The hypothesis of this study is that leukocyte endothelial adhesion represents a novel biomarker for diabetic retinopathy. Specifically, this proposal will test whether leukocyte endothelial adhesion 1) Is associated with different stages of diabetic retinopathy severity; 2) Is affected by intensive glycemic control, cumulative glycemia, diabetes duration or other factors; 3) Predicts the progression of diabetic retinopathy; or 4) Is associated with other micro and macro vascular complications including nephropathy, neuropathy and cardiovascular disease. The study objectives will be accomplished through the use of a large prospective clinical study of well-characterized human subjects with diabetic retinopathy. Accordingly, this study will leverage samples from all 1,441 subjects of the DCCT/EDIC cohort, a landmark clinical study of diabetic retinopathy. The DCCT/EDIC study prospectively followed subjects over a twenty-five year period. Access to disease relevant human tissue associated with exquisitely characterized prospective clinical data from thousands of human subjects with diabetic retinopathy is invaluable. An innovative high-throughput assay will be used to determine individual levels of leukocyte endothelial adhesion for all 1,441 DCCT/EDIC study subjects. In summary, this proposal will use human samples from a large clinical study to determine whether a novel cellular property, leukocyte endothelial adhesion, correlates with diabetic retinopathy outcomes. The ability to study and treat diabetic retinopathy has been hampered considerably by lack of a unique, valid and translatable biomarker for the disease. If successful, work from this study would establish an individual's level of leukocyte endothelial adhesion as a novel biomarker and independent risk factor for diabetic retinopathy. Such findings could have immediate clinical implications that bear on the diagnosis, management, and treatment of this condition.

Public Health Relevance

This proposal will use human samples from a large clinical study to determine whether a novel cellular property, leukocyte endothelial adhesion, correlates with diabetic retinopathy outcomes. The ability to study and treat diabetic retinopathy has been considerably hampered by lack of a unique, valid and translatable biomarker for the disease. If successful, work from this study would establish an individual's level of leukocyte endothelial adhesion as a novel biomarker and independent risk factor for diabetic retinopathy.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY023644-04
Application #
9554925
Study Section
Diseases and Pathophysiology of the Visual System Study Section (DPVS)
Program Officer
Shen, Grace L
Project Start
2015-09-30
Project End
2020-08-31
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Al-Khersan, Hasenin; Kwong, Alan; Grassi, Michael A (2018) Mutations in MERTK are not associated with age-related macular degeneration. Int Ophthalmol :
Metelitsina, Tatyana I; Sheth, Veeral S; Patel, Shuchi B et al. (2017) PERIPHERAL RETINOPATHY ASSOCIATED WITH APLASTIC ANEMIA. Retin Cases Brief Rep 11:108-110
Al-Khersan, Hasenin; Hain, Tim; Grassi, Michael A (2017) Vision Loss in a Teenage Girl With Postconcussion Syndrome. JAMA Ophthalmol 135:75-76
Al-Khersan, Hasenin; Shah, Kaanan P; Jung, Segun C et al. (2017) A novel MERTK mutation causing retinitis pigmentosa. Graefes Arch Clin Exp Ophthalmol 255:1613-1619
Metelitsina, Tatyana I; Waggoner, Darrel J; Grassi, Michael A (2016) BATTEN DISEASE CAUSED BY A NOVEL MUTATION IN THE PPT1 GENE. Retin Cases Brief Rep 10:211-3
Grassi, Michael A; Rao, Vidhya R; Chen, Siquan et al. (2016) Lymphoblastoid Cell Lines as a Tool to Study Inter-Individual Differences in the Response to Glucose. PLoS One 11:e0160504
Garcia-Gonzalez, José María; Neiweem, Ashley E; Grassi, Michael A (2015) Cobalamin C Deficiency-Associated Pigmentary Retinopathy. JAMA Ophthalmol 133:e152161