Sex difference in conjunctival epithelial cell response and their profile of extracellular bioactive lipids duringallergic inflammation

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PROJECT SUMMARY Sex difference in the profile of extracellular bioactive lipid mediators, especially that of the specialized pro-resolving and proinflammatory lipid mediators (SPMs and PIMs, respectively), during inflammation is significantly correlated to sex differences in the cellular response, and prevalence and the severity of various inflammatory diseases, including ocular surface inflammation. As an ocular surface tissue, conjunctival epithelium lines the inside of the eyelids and covers the sclera, thus providing stability to the anterior segment of the eye. The conjunctival goblet cells (CGCs) secrete mucins to wet and protect the ocular surface, of which under- or over-secretion due to inflammation causes visual disturbance. Therefore, time-dependent resolution of conjunctival inflammation is critical for a transparent cornea and clear vision. Our exciting preliminary data show that CGCs secrete SPMs and PIMs as extracellular vesicle (EV) cargo to maintain homeostasis, and the amount of SPMs dramatically increases during a histamine-mediated allergic response. Interestingly, the increase was only observed in EVs of female CGCs but not males. EVs collected from males under the same condition showed a slight decrease in the amounts of SPMs compared to the control. To further investigate these novel findings, this research proposal aims to study the sex differences in the cellular response of human CGCs and the bioactive lipid mediators that CGCs secrete via EVs during histamine-mediated allergic inflammation. For Aim 1, we will identify sex differences in the cellular response by quantifying the magnitude of mucin secretion and change in intracellular Ca2+ concentration, and measuring the activation of intracellular enzymes involved in the allergic response and synthesis of bioactive lipid mediators. For Aim 2, we will determine the sex differences in the profile of extracellular bioactive lipid mediators during the allergic response by analyzing the type and amount of SPMs and PIMs loaded into EVs, and their time course of secretion. The success of this study will provide new insights into the bioactive lipid-mediated ocular surface protective mechanism generated by the conjunctiva and the basis for a tailored sex-dependent, lipid-based therapeutic approach in the management of vision-debilitating ocular surface diseases.