Anterior Segments Diseases

Dry eye disease is a multifactorial ocular disease associated with substantial medical expenses and significant impairments of quality of life and workplace productivity. Socioeconomic estimates attribute an annual burden of $50 billion to U.S. society. Current management of dry eye disease involves anti-inflammatory and immunomodulatory drugs, such as ophthalmic cyclosporine (Restasis®) or the integrin lymphocyte function-associated antigen-1 (LFA-1) antagonist, lifitegrast (Xiidra®).  Surgical management offers the last resort when topical drugs fail to alleviate dry eye symptoms.

Clinically, dry eye disease is an umbrella term that describes ocular surface disease associated with various different etiologies, and encompasses aqueous deficient and evaporative dry eye, ocular graft-vs-host disease (a complication of bone marrow transplant), autoimmune dry eye (e.g. associated with Sjögren’s syndrome), and chronic ocular symptoms associated allergies.

One major challenge in drug discovery for dry eye disease has been a lack of standardized experimental methods and paradigms that can help elucidate the pathophysiology of the various facets of the disease but also to test drug candidates such that these preclinical data can be predictive for success in phase trials

The major focus of our research program has been to rigorously refine existing models for dry eye disease, standardize and validate them against the clinical standard of care for dry eye disease, Restasis®, and to use pharmacological agents and drug candidates to both, gain mechanistic insight into the disease pathology and accelerate drug discovery for dry eye disease.

We currently have several projects on dry eye disease in the lab and are actively recruiting graduate students and postdocs to join our group:

1. Immunotherapy for Dry Eye Disease – funded by NIH R24, #EY032440 (2021), in collaboration with Sandeep Jain, MD at University of Illinois at Chicago
2. Effects of chronic alcohol consumption on development of ocular surface disease – funded by NIH T32, #AA013527 and Illinois Society for the Prevention of Blindness
3. Development of Environmental Dry Eye Disease Models Mimicking Burn Pit Smoke Exposure – funded by Fight for Sight, Illinois Society for the Prevention of Blindness
4. Antioxidant Therapy for Dry Eye Disease – previously funded by Fight for Sight and Illinois Society for the Prevention of Blindness

Key Publications:

1. Ghosh AK, Čėsna R, Neverauskas D, Žiniauskaitė A, Iqbal S, Eby JM, Ragauskas S, Kaja S. Dietary Alcohol Consumption Elicits Corneal Toxicity Through the Generation of Cellular Oxidative Stress. J Ocul Pharmacol Ther. 2023. 10.1089/jop.2022.0187. 
2. Ghosh AK, Bacellar-Galdino M, Iqbal S, Pappenhagen NE, Kaja S. Topical Porphyrin Antioxidant Protects Against Ocular Surface Pathology in a Novel Rabbit Model for Particulate Matter-Induced Dry Eye Disease. J Ocul Pharmacol Ther. 2022; 38: 294-304. 10.1089/jop.2021.0131
3. Ghosh AK, Thapa R, Hariani HN, et al. Poly(lactic-co-glycolic acid) Nanoparticles Encapsulating the Prenylated Flavonoid, Xanthohumol, Protect Corneal Epithelial Cells from Dry Eye Disease-Associated Oxidative Stress. Pharmaceutics. 2021; 13: 1362. 10.3390/pharmaceutics13091362
4. Žiniauskaitė A, Ragauskas S, Ghosh AK, Thapa R, Roessler AE, Koulen P, Kalesnykas G, Hakkarainen JJ, and Kaja S, Manganese(III) tetrakis(1-methyl-4-pyridyl) porphyrin, a superoxide dismutase mimetic, reduces disease severity in in vitro and in vivo models for dry-eye disease. Ocul Surf. 2019; 17: 257-264. 10.1016/j.jtos.2019.02.006
5. Žiniauskaite A, Ragauskas S, Hakkarainen JJ, Rich CC, Baumgartner R, Kalesnykas G, Albers DS, and Kaja S, Efficacy of Trabodenoson in a Mouse Keratoconjunctivitis Sicca (KCS) Model for Dry-Eye Syndrome. Invest Ophthalmol Vis Sci. 2018; 59: 3088-3093. 10.1167/iovs.18-24432
6. Hakkarainen JJ, Reinisalo M, Ragauskas S, Seppänen A, Kaja S, and Kalesnykas G, Acute cytotoxic effects of marketed ophthalmic formulations on human corneal epithelial cells. Int J Pharm. 2016; 511: 73-78. 10.1016/j.ijpharm.2016.06.135

Glaucoma is the leading cause of irreversible blindness worldwide and causes a substantial burden on the affected individual, caregivers, and society alike. It is estimated that approx. 6 mi Americans are affected by glaucoma. 
Primary open-angle glaucoma (POAG) is the most common form of glaucoma and defined as any glaucoma in which the angle of the anterior chamber remains open, but the exit of aqueous through the trabecular meshwork is diminished. This leads to an abnormal balance of secretion and drainage of aqueous through the trabecular meshwork and uveoscleral outflow pathways, ultimately resulting in elevated intraocular pressure (IOP). While currently available therapies can lower IOP to prevent further ON damage, visual field loss and death of both RGCs and ONHAs continues, highlighting the need for novel treatment strategies. 
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Optic nerve head astrocytes are the major cell type in the non-myelinated region of the optic nerve head and provide structural, metabolic and trophic support to the optic nerve. Under pathological conditions, such as primary open angle glaucoma, these cells undergo a process called reactive astrocytosis (or astrogliosis). The ensuing changes in the structural and biomechanical properties of the optic nerve head manifest as optic nerve “cupping” and are used clinically as a diagnostic criterion for the progression of glaucoma.
In our Laboratory, we are particularly interested in deciphering the mechanisms contributing to the reactive astrocytosis and to discovering novel drug targets that can stop the progressive cascade of glaucomatous changes. 

We currently have several ongoing projects on glacucoma in the lab:

1. Molecular mechanisms underlying reactive astrocytosis and fibrosis in the glaucomatous eye –funded by AcuiSee, Inc., The Glaucoma Foundation and Illinois Society for the Prevention of Blindness, in collaboration with Evan B. Stubbs Jr, Ph.D. at Edward Hines Jr. VA Hospital and Shandiz Tehrani, M.D. at Oregon Health Sciences University
2. Effects of Lysyl Oxidase-Like 1 (LOXL1) on Reactive Astrocytosis and Neuron-Glia Signaling – funded by Illinois Society for the Prevention of Blindness

Key Publications:

1. Hariani HN, Ghosh AK, Rosen SM, Tso HY, Kessinger C, Zhang C, Jones WK, Sappington RM, Mitchell CH, Stubbs EB Jr, Rao VR, Kaja S. Lysyl oxidase like-1 deficiency in optic nerve head astrocytes elicits reactive astrocytosis and alters functional effects of astrocyte derived exosomes. Exp Eye Res. 2024;240: 109813. doi: 10.1016/j.exer.2024.109813. PMID: 38331016.
2. Ghosh AK, Rao VR, Wisniewski VJ, Zigrossi AD, Floss J, Koulen P, Stubbs EB, Jr., and Kaja S, Differential Activation of Glioprotective Intracellular Signaling Pathways in Primary Optic Nerve Head Astrocytes after Treatment with Different Classes of Antioxidants. Antioxidants (Basel). 2020; 9: 10.3390/antiox9040324, IF: 5.014, PMID: 32316287
3. Kaja S, Payne AJ, Naumchuk Y, Levy D, Zaidi DH, Altman AM, Nawazish S, Ghuman JK, Gerdes BC, Moore MA, and Koulen P, Plate reader-based cell viability assays for glioprotection using primary rat optic nerve head astrocytes. Exp Eye Res. 2015; 138: 159-166. 10.1016/j.exer.2015.05.023, IF: 3.011, PMID: 26048476
4. Kaja S, Payne AJ, Patel KR, Naumchuk Y, and Koulen P, Differential subcellular Ca2+ signaling in a highly specialized subpopulation of astrocytes. Exp Neurol. 2015; 265: 59-68. 10.1016/j.expneurol.2014.12.014, IF: 4.691, PMID: 25542978