Corneal neovascularization is a vision-threatening condition affecting ~1.4 million individuals each year in the United States alone. It is associated with a wide range of ocular disorders and is the major cause of corneal graft rejection. Indeed, the frequency of rejection reaches as high as 90% for corneal grafts placed in high-risk vascularized host beds. In addition to blood vessels (BV), lymphatic vessels (LV) also play a key role in graft rejection and other ocular disorders provoked by immune response. The presence of BV and LV essentially abrogates the immune privilege status of the cornea. The goal of this project is to understand the molecular mechanisms that regulate hemangiogenesis (HA) and lymphangiogenesis (LA) in the cornea and to develop effective strategies to prevent the growth of blood and lymphatic vessels in the cornea. HA and LA are predominantly mediated by a family of vascular endothelial cell growth factor (VEGF) receptors and integrins. In a recent study, we demonstrated that a carbohydrate- binding protein, galectin-3 (Gal3) is a mediator of the VEGF-mediated angiogenic response. Also, in a pilot study, we have shown that Gal3 promotes LA in vitro and in vivo. In the proposed study, we will characterize the mechanism by which galectins modulate HA and LA and will determine whether galectins can be exploited to prevent corneal neovascularization.
In Aim 1, we will determine whether the function of select VEGF receptors (VEGFR-2 and -3) and integrins (1v23, 1v25, 1521, 1421, 1921, 1121), well- defined for their role in HA and/or LA, is modulated by Gal3. Specifically, we will determine: (i) which specific VEGFRs and integrins bind to Gal3 and (ii) whether the binding activates the receptor and transmembrane signaling, and, if so, whether Gal3-mediated phosphorylation and activation of one or more VEGFRs is independent of its ligand, VEGF.
In Aim 2, we will determine whether any other members of the galectin family, besides Gal3, influence HA and/or LA. After establishing, which specific galectins are proangiogenic, we will characterize the molecular mechanism by which these galectins influence HA and/or LA, and will determine whether suture-induced corneal neovascularization is reduced in the select galectin(s) knockout mice.
In Aim 3, we will determine whether specific inhibitors of galectins can be used to prevent the growth of BV and LV in the mouse model of suture-induced inflammatory HA and LA. It is our hope that this study will lead to the development of novel, more effective strategies for corneal allograft survival as well as for prevention and regression of BV and LV in numerous other inflammatory disorders of the ocular surface. The impact of the proposed study extends far beyond diseases of the cornea because HA and LA dysfunctions have been found in numerous diseases including neovascular age-related macular degeneration, diabetes, cancer, AIDS and in all solid organ transplants.
Corneal neovascularization is a vision-threatening condition affecting ~1.4 million individuals each year in the U.S. alone. It leads to permanent blindness in many, and, at present, there are no means to restore sight in affected patients. The ultimate goal of the project is to develop novel, state-of-the-art, strategies for corneal allograft survival, as well as for treatment of numerous other inflammatory disorders of the ocular surface including corneal infections, trauma and dry eye.
|Chen, Wei-Sheng; Cao, Zhiyi; Leffler, Hakon et al. (2017) Galectin-3 Inhibition by a Small-Molecule Inhibitor Reduces Both Pathological Corneal Neovascularization and Fibrosis. Invest Ophthalmol Vis Sci 58:9-20|
|Chen, Wei-Sheng; Cao, Zhiyi; Sugaya, Satoshi et al. (2016) Erratum: Pathological lymphangiogenesis is modulated by galectin-8-dependent crosstalk between podoplanin and integrin-associated VEGFR-3. Nat Commun 7:12063|
|Sampson, James F; Suryawanshi, Amol; Chen, Wei-Sheng et al. (2016) Galectin-8 promotes regulatory T-cell differentiation by modulating IL-2 and TGF? signaling. Immunol Cell Biol 94:213-9|
|Chen, Wei-Sheng; Cao, Zhiyi; Sugaya, Satoshi et al. (2016) Pathological lymphangiogenesis is modulated by galectin-8-dependent crosstalk between podoplanin and integrin-associated VEGFR-3. Nat Commun 7:11302|
|Cao, Zhiyi; Saravanan, Chandrassegar; Chen, Wei-Sheng et al. (2015) Examination of the role of galectins in cell migration and re-epithelialization of wounds. Methods Mol Biol 1207:317-26|
|Sugaya, Satoshi; Chen, Wei-Sheng; Cao, Zhiyi et al. (2015) Comparison of galectin expression signatures in rejected and accepted murine corneal allografts. Cornea 34:675-681|
|Sampson, James F; Hasegawa, Eiichi; Mulki, Lama et al. (2015) Galectin-8 Ameliorates Murine Autoimmune Ocular Pathology and Promotes a Regulatory T Cell Response. PLoS One 10:e0130772|
|Chen, Wei-Sheng; Cao, Zhiyi; Truong, Laetitia et al. (2015) Fingerprinting of galectins in normal, P. aeruginosa-infected, and chemically burned mouse corneas. Invest Ophthalmol Vis Sci 56:515-25|
|Panjwani, Noorjahan (2014) Role of galectins in re-epithelialization of wounds. Ann Transl Med 2:89|
|Markowska, Anna I; Cao, Zhiyi; Panjwani, Noorjahan (2014) Glycobiology of ocular angiogenesis. Glycobiology 24:1275-82|
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