Hormonal dynamics and extracellular vesicle function in keratoconus: exploring pathophysiology and developing targeted therapies

The National Eye Institute, part of the Department of Health and Human Services National Institutes of Health, awarded $132,837 to The Schepens Eye Research Institute, Inc. on July 1, 2026, under the Vision Research program (CFDA 93.867) to investigate hormonal dynamics and extracellular vesicle function in keratoconus.

The research addresses keratoconus pathophysiology by examining how follicle-stimulating hormone, luteinizing hormone, estrogen, and progesterone—individually or in combination—influence collagen degradation in the cornea. The study will analyze tear samples from keratoconus and non-keratoconus patients (male and female) and utilize a 3D collagen hydrogel model of corneal epithelium and keratocytes to identify spatiotemporal regulation of matrix metalloproteinases (MMP-2/9) and specific signaling pathways involved in disease progression. The work will also investigate the functional roles of tear-derived extracellular vesicles and their molecular constituents (RNA and protein) as potential disease indicators. Research outcomes could lead to developing topical therapeutic agents to mitigate hormone-mediated corneal thinning.

Performance occurs in Boston, Massachusetts, with a period of performance from July 1, 2026 through June 30, 2028. This is a project grant, a competitive research award under the Vision Research program, which seeks to drive innovative research to understand the eye and visual system, prevent and treat vision diseases, and expand opportunities for people who are blind or require vision rehabilitation.

Abstract

Keratoconus (KC) is a progressive corneal ectasia characterized by the degradation of stromal collagen. The pathophysiology of KC is intricate, involving a range of biochemical, immunological, metabolic, endocrinological, and genetic factors. Because of this complexity, the exact origin of the disease-whether IT arises from the epithelium or the stroma-remains debated due to the lack of an appropriate disease model. KC generally begins after puberty, and can be exacerbated by pregnancy, and rarely progresses after menopause. Furthermore, there is a critical absence of reliable prognostic markers that could clarify why some KC patients experience faster progression than others. Our study will assess the impact of hormones such as follicle-stimulating hormone (FSH), luteinizing hormone (LH), estrogen, and progesterone-individually or in combination-on collagen degradation. To address these challenges, we will utilize tears from both KC and non- KC patients (male and female), along with our developed 3D collagen hydrogel model of corneal epithelium and keratocytes. We will focus on the spatiotemporal regulation of matrix metalloproteinases (MMP-2/9) to identify the specific signaling pathways involved this endeavor could lead to developing topical therapeutic agents to mitigate hormone-mediated corneal thinning. Previous research has used KC tears to identify potential biomarkers for the disease, and extracellular vesicles (EVS) have been suggested as possible disease indicators. Male KC patients secrete increased EVS compared to their female counterparts. However, the functional roles of tear-derived EVS and their molecular constituents (RNA and protein) have yet to be explored. In this study, we will utilize tears KC and non-KC patients, along with our developed 3D collagen hydrogel model, to investigate how specific KC-associated mutations (lysyl oxidase RS2956540 and MMP9-RS17576) influence the differential sorting of mirna in EVS. We will also examine the role of mirna derived EVS from the tears of KC patients in the pathogenesis of corneal ectasia. Overall, the use of our 3D corneal model will allow US to identify cell-specific responses to hormones and EVS, providing insights into the origins of the disease pathology.