Diabetic retinopathy has been the leading cause of blindness in the United States since 1974. It is manifest by progressive changes in the microvasculature of the diabetic eye, leading to intravitreal hemorrhages, retinal edema, neovascularization, and detachments. Along with the retina, cornea, lens and iris are also affected by diabetes. Many diabetics suffer from diabetic keratopathy that includes recurrent erosions, epithelial fragility, abnormal wound healing and increased susceptibility to injury. Altered epithelial-stromal interactions and epithelial basement membrane (BM) defects likely contribute to diabetic keratopathy. Despite clinical importance of diabetic corneal disease, the molecular mechanisms of this complication are not understood. In our preliminary studies, the expression of many BM components and proteinases has been analyzed in normal and diabetic human corneas. We show that: 1. Diabetic retinopathy (DR) corneas have severely decreased epithelial BM immunostaining for laminin-1, laminin-10, nidogen-1/entactin, and for epithelial integrin alpha3 beta1; 2. Gene expression of BM proteins and integrin alpha3 beta1 is not changed in diabetic and DR corneal epithelium; 3. Gene and protein expression of matrix metalloproteinase (MMP)-10 increases in diabetic and DR corneal epithelium and stroma, and MMP-3 expression increases in diabetic and DR corneal stroma. The data suggest that major components of corneal epithelial BM are altered in diabetes and especially DR due to elevated activity of specific proteinases, e.g., of MMP-1O that is expressed in the epithelium. Our hypothesis is that corneal epithelial BM in diabetes and DR undergoes degradation by elevated proteinases, notably by MMP-10. Proteinase expression and activity may be stimulated by specific growth factors activated by diabetic microenvironment. These alterations may constitute the molecular mechanism of corneal epithelial abnormalities in diabetes.
Specific Aim 1. To characterize the effect of MMP-10 on the integrity of corneal epithelial BM and integrin alpha3 beta1 and on wound healing in organ-cultured human corneas.
Specific Aim 2. To identify by gene array analysis growth factors and cytokines abnormally expressed in diabetic and DR corneas and examine their effects on MMP-10 and wound healing in normal organ-cultured corneas.
Specific Aim 3. To assess by gene array analysis the expression levels of various proteinases in diabetic, DR and normal human corneas. Identify and analyze additional proteinases with elevated expression in diabetic corneas.
Specific Aim 4. To attempt blocking BM and integrin degradation in human diabetic and DR organ-culture corneas. Neutralizing antibodies to specific growth factors and proteinases (primarily, MMP-10), and various MMP inhibitors including clinically approved tetracyclines will be tested in organ-cultured corneas. These studies could lead to the development of novel therapeutics that would block the progression of diabetic keratopathy.
|Leszczynska, Aleksandra; Kulkarni, Mangesh; Ljubimov, Alexander V et al. (2018) Exosomes from normal and diabetic human corneolimbal keratocytes differentially regulate migration, proliferation and marker expression of limbal epithelial cells. Sci Rep 8:15173|
|Ljubimov, Alexander V (2017) Diabetic complications in the cornea. Vision Res 139:138-152|
|Daliri, Karim; Ljubimov, Alexander V; Hekmatimoghaddam, Seyedhossein (2017) Glaucoma, Stem Cells, and Gene Therapy: Where Are We Now? Int J Stem Cells 10:119-128|
|Kulkarni, Mangesh; Leszczynska, Aleksandra; Wei, Gabbie et al. (2017) Genome-wide analysis suggests a differential microRNA signature associated with normal and diabetic human corneal limbus. Sci Rep 7:3448|
|Ljubimova, Julia Y; Sun, Tao; Mashouf, Leila et al. (2017) Covalent nano delivery systems for selective imaging and treatment of brain tumors. Adv Drug Deliv Rev 113:177-200|
|Saghizadeh, Mehrnoosh; Kramerov, Andrei A; Svendsen, Clive N et al. (2017) Concise Review: Stem Cells for Corneal Wound Healing. Stem Cells 35:2105-2114|
|Ljubimov, Alexander V (2017) Cell Therapy for Age-Related Macular Degeneration: A New Vision for the Bone Marrow? Mol Ther 25:832-833|
|Kramerov, Andrei A; Saghizadeh, Mehrnoosh; Ljubimov, Alexander V (2016) Adenoviral Gene Therapy for Diabetic Keratopathy: Effects on Wound Healing and Stem Cell Marker Expression in Human Organ-cultured Corneas and Limbal Epithelial Cells. J Vis Exp :e54058|
|Kramerov, Andrei A; Ljubimov, Alexander V (2016) Stem cell therapies in the treatment of diabetic retinopathy and keratopathy. Exp Biol Med (Maywood) 241:559-68|
|Chou, Szu-Ting; Patil, Rameshwar; Galstyan, Anna et al. (2016) Simultaneous blockade of interacting CK2 and EGFR pathways by tumor-targeting nanobioconjugates increases therapeutic efficacy against glioblastoma multiforme. J Control Release 244:14-23|
Showing the most recent 10 out of 41 publications