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Summer Research Fellowship Programme of India's Science Academies

Involvement of CXCR4 in diabetic retinopathy

Ms. Natasha Kelkar

Institute of Bioinformatics and Biotechnology, Savitribai Phule Pune University, Ganeshkhind Road, Pune 411007

Dr. Inderjeet Kaur

Kallam Anji Reddy Molecular Genetics Lab, Brien Holden Eye Researh Centre, LV Prasad Eye Institute, Banjara Hills, Hyderabad 500034

Abstract

C-X-C chemokine Receptor type 4 is a chemokine family of GPCRS. It plays an important role in central nervous system homeostasis and neuroprotection and neuroglial communication. CXCR4+ cells are involved in many inflammatory and angiogenic conditions mainly recruited by its ligand SDF-1. It also has a role in M1 macrophage polarization, causing proinflammatory cytokine release and damage to the tissue. HIF1-α controls the activation of CXCR4 at the transcriptional level and its expression under hypoxia/ischemia. Hypoxia acts as a major factor in many neurovascular diseases such as retinopathy of prematurity, age related macular degeneration, diabetic retinopathy (DR) etc. DR is a serious neurovascular complication of diabetes and causes catastrophic loss of vision if untreated. The presence of a low/high grade inflammation is one of the prominent features of DR. Studies have also shown the activation of resident macrophages known as microglia in diabetic retina, much before the development of DR complications. CXCR4 has a major role in inducing the inflammatory and immune responses and activated microglial cells in DR are inflammatory and elicit immune response. Activated microglia secrete complement C3 as a part of the immune response and complement activation is known in the DR. Studies have shown that the activated complement fragments interact with CXCR4 and helps in mobilization of the cells. But none of the studies have addressed the interactions of microglial CXCR4 and C3 in DR and its role in disease progression. Hence, we hypothesized that C3 activation in microglia enhances CXCR4 expression and may recruit more microglial cells and worsen the disease pathogenesis. We aim to estimate the level of CXCR4 in the DR patients and to identify its regulation by immune system proteins like complement C3. The level of CXCR4 expression in DR vitreous will be studied through western blotting compared to non-diabetic controls. Also, the change in expression of these genes in the blood of patients suffering from the disease would be checked by qRT PCR. The expression of these in the retina of a cadaver suffering from diabetes would be checked by westen blotting and immunofluorescence. Also, we will study the expression of CXCR4 and its correlation with C3 expression in the microglial and the retinal pigement epithelial cells under the conditions of hypoxia and hyperglycemia by PCR, western blotting and immunofluorescence.

Keywords: inflammation, vitreous, microglia, retinal pigment epithelium, complement

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