The Panjwani laboratory specializes in glycobiology and in investigating the role carbohydrate-binding proteins in diseases of the eye. Carbohydrate-binding proteins play a pivotal role in fundamental biological processes. One of the most well-known examples is the role of selectins in extravasation of leukocytes from the blood to the sites of inflammation. The figure below illustrates this phenomenon.
Figure 1. Carbohydrate-binding proteins have been shown to play a pivotal role in fundamental biological processes. One of the most well-known examples is the role of the most well-known examples is the role of selectins in extravasation of leukocytes from the blood to the sites of inflammation.
We study the role of carbohydrate-binding proteins, galectins, in the pathogenesis of the diseases of the cornea and retina including persistent epithelial defects, corneal and choroidal neovascularization, corneal graft rejection and infections. All projects in the lab have a solid basic science component to understand cell biological, biochemical and immunological mechanisms of corneal infections, wound healing, angiogenesis, and scar tissue formation, and are disease-oriented with a focus on translational research to find better, novel ways to treat blinding diseases of the eye. We have the unique expertise, and availability of unique set of mice and reagents needed to successfully pursue our studies aimed at the characterization of the role of galectins in the pathogenesis of the diseases of the eye.
It is well established that transmembrane integrin receptors and growth factor receptors play a crucial role in re-epithelialization of wounds and angiogenesis. Although, almost all cell surface receptors including integrins, growth factor receptors and cytokine receptors are glycosylated proteins, they have been relatively under-investigated in the context of their glycosylation patterns. Our studies represent the leading edge of our current biochemical understanding of how the glycosylation pattern of cell surface receptors regulates their function. For example, in recent studies we have shown that: (i) a carbohydrate binding protein, Gal-3, promotes re-epithelialization of corneal wounds, and that, it does so by activating α3β1-integrin–Rac1 signaling in epithelial cells, (ii) Gal-3 modulates VEGF- and bFGF-mediated angiogenesis by binding to the N-glycans of integrin avb3, and subsequently activating the signaling pathways that promote the growth of new blood vessels, and (iii) pathological lymphangiogenesis is modulated by galectin-8 (Gal-8)-dependent crosstalk between podoplanin and integrin-associated VEGFR-3. These findings have broad implications for developing novel therapeutic strategies for conditions resulting from pathological hem- and lymph-angiogenesis in both ocular diseases such as corneal graft rejection and choroidal neovascularization as well as nonocular diseases such as cancer metastasis and solid organ transplant rejection. Our studies are highly clinically relevant and have resulted in several patent applications targeting galectins for prevention of pathological hem- and lymph-angiogenesis in ocular tissues.
Choroidal neovascularization and associated subretinal scarring (e.g. age-related macular degeneration) as well as the growth of abnormal blood vessels in the clear cornea and corneal scarring are serious conditions that can lead to a profound decline in vision or vision loss. There currently are no Food and Drug Administration–approved drugs that selectively reduce scar formation. Recent studies have demonstrated that Gal-3 promotes angiogenesis (see previous section) as well as fibrosis, and that it does so by independent mechanisms. Therefore, Gal-3 is an ideal candidate to target for developing dual-benefit drugs to control both neovascularization and fibrosis of ocular tissues. Our lab has already characterized the mechanism by which Gal-3 promotes angiogenesis. Currently, we are characterizing the mechanism by which Gal-3 modulates development of scar tissue, and are also conducting studies to identify the most potent Gal-3 inhibitors to develop novel strategies for reduction of corneal and subretinal fibrosis.
Recently, we have conducted a very fruitful set of studies to characterize the role of galectins in immunopathology of Pseudomonas keratitis, autoimmune uveitis, and differentiation of Treg cells. In another study, we have made an exciting observation that Gal-8 knockout mice are resistant to P. aeruginosa (PA) infection. In an effort to understand the mechanisms that render Gal-8 KO mice resistant to PA keratitis, our working hypothesis is that Gal-8 has the capacity to dampen the activation of TLR pathway and/or inflammasome pathway. Overall goal of this project is to characterize the role of Gal-8 in the regulation of PA-induced immunopathology, and to develop effective strategies for prevention and regression of uncontrolled inflammatory response that results in extensive damage to the cornea and visual impairment.