The incidence of diabetes world-wide, is expected to reach epidemic proportions by 2025. Progression of diabetic retinopathy often results in diabetic macular edema, which is a consequence of the breakdown of the blood-retinal barrier, increased retinal vascular permeability and leakage of plasma from small blood vessels in the macula leading to loss of central vision. The degree of hyperglycemia and duration of diabetes have been shown to be good predictors of retinal complications. Intervention studies have determined that while intensive treatment of diabetes reduced the development of proliferative diabetic retinopathy it was associated with an increased risk of mortality from cardiovascular disease (Ismail-Beigi June 29, 2010 Lancet online) as well as with a higher morbidity risk from hypoglycemic episodes. We reason that it is critical to identify a downstream glycemic target that causes increased retinal vascular permeability that could be targeted therapeutically without the additional risks associated with intensive treatment of the hyperglycemia. Betacellulin is a 32 kD member of the epidermal growth factor family that is produced by proliferating ? cells of the islets and promotes regeneration of pancreatic ? cells. We hypothesize a role for betacellulin in the retinal vascular complications associated with diabetes based on our preliminary studies, which show that diabetic mice have accentuated retinal vascular permeability with a concomitant increased expression of a cleaved soluble form of betacellulin (s-Btc) in the retina. Intravitreal injection of betacellulin induced retinal hemorrhage and increased vascular permeability in normoglycemic and hyperglycemic mice. A disintegrin and metalloproteinase, ADAM-10 (which plays a role in the cleavage of betacellulin), is increased in the retinae of diabetic mice and humans with diabetic retinopathy. Based on these preliminary results we hypothesize that betacellulin contributes to increased retinal vascular permeability and the pathogenesis of diabetic macular edema.

Public Health Relevance

Retinopathy leading to vision loss is a major long-term consequence for a majority of patients with diabetes (both type I and type II). Increased retinal vascular permeability underlies the pathology of diabetic retinopathy. Under normal physiological conditions the retinal vessels form a tight barrier by virtue of tight junctions that allow a strict control of fluids and solutes that cross the blood-retinal barrier. Loss of this barrier function leads to leaky vessels and macular edema. This project will determine the role of betacellulin and ADAM (disintegrin and metalloproteinase)-10 in the development of retinal vascular leakage. Results from these studies will contribute to a better understanding of the molecular mechanisms that are involved in the formation and maintenance of the blood retinal barrier and may lead to the future development of therapeutic modalities to prevent the devastating vision loss that accompanies diabetes.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
Project #
Application #
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Shen, Grace L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Cleveland Clinic Lerner
Other Basic Sciences
Schools of Medicine
United States
Zip Code
Pollock, Lana M; Xie, Jing; Bell, Brent A et al. (2018) Retinoic acid signaling is essential for maintenance of the blood-retinal barrier. FASEB J 32:5674-5684
Charette, Jeremy R; Earp, Sarah E; Bell, Brent A et al. (2017) A mutagenesis-derivedLrp5mouse mutant with abnormal retinal vasculature and low bone mineral density. Mol Vis 23:140-148
Qi, Jian Hua; Anand-Apte, Bela (2015) Tissue inhibitor of metalloproteinase-3 (TIMP3) promotes endothelial apoptosis via a caspase-independent mechanism. Apoptosis 20:523-34
Kotb, Ahmed M; Müller, Tobias; Xie, Jing et al. (2014) Simultaneous assessment of glomerular filtration and barrier function in live zebrafish. Am J Physiol Renal Physiol 307:F1427-34
Bell, Brent A; Xie, Jing; Yuan, Alex et al. (2014) Retinal vasculature of adult zebrafish: in vivo imaging using confocal scanning laser ophthalmoscopy. Exp Eye Res 129:107-18
DiCicco, Rose M; Bell, Brent A; Kaul, Charles et al. (2014) Retinal regeneration following OCT-guided laser injury in zebrafish. Invest Ophthalmol Vis Sci 55:6281-8
Sugimoto, Masahiko; Cutler, Alecia; Shen, Bailey et al. (2013) Inhibition of EGF signaling protects the diabetic retina from insulin-induced vascular leakage. Am J Pathol 183:987-95
Hewing, Nina Jasmin; Weskamp, Gisela; Vermaat, Joost et al. (2013) Intravitreal injection of TIMP3 or the EGFR inhibitor erlotinib offers protection from oxygen-induced retinopathy in mice. Invest Ophthalmol Vis Sci 54:864-70
Morais, Christudas; Ebrahem, Quteba; Anand-Apte, Bela et al. (2012) Altered angiogenesis in caveolin-1 gene-deficient mice is restored by ablation of endothelial nitric oxide synthase. Am J Pathol 180:1702-14
Sugimoto, Masahiko; Cutler, Alecia; Grossman, Gregory et al. (2012) Regulation of retinal vascular permeability by betacellulin. Adv Exp Med Biol 723:293-8

Showing the most recent 10 out of 13 publications