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Mindy Call, Katy Fischesser, Matthew Lunn, Winston Kao; Notch regulation of PPAR-gamma and development of meibomian gland dysfunction. Invest. Ophthalmol. Vis. Sci. 2013;54(15):924.
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© ARVO (1962-2015); The Authors (2016-present)
Meibomian gland dysfunction (MGD) is a chronic, diffuse abnormality of the meibomian glands, which is characterized by terminal duct obstruction and/or qualitative/quantitative changes in glandular secretion resulting in alterations of the tear film, eye irritation and inflammation. One particular molecule thought to play an important role in lipid secretion is peroxisome proliferator activated receptor gamma (PPARλ). Given the importance of PPARλ in lipid metabolism, this study aims to elucidate its role in meibomian gland formation/function and the development of MGD. The hypothesis is that loss of PPARλ will disrupt meibomian gland formation/function resulting in a hyposecretory state. In addition this study will examine the role of Notch signaling in regulating PPARλ expression.
Transgenic animals, utilizing both Le-cre and K14-rtTA driver mice, were used to ablate PPARλ and Jag1 and to express dnMAML. Animals were examined for signs of MGD/dry eye via tear solution assessment, HRT II, slit lamp, lissamine green staining, oil red O staining and lyve 1 staining. In addition, eyes were collected at various time points to assess expression of Notch signaling components. All reported research was conducted in compliance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research and approved by the IACUC of the University of Cincinnati.
Loss of PPARλ resulted in abnormalities in meibomian gland morphogenesis leading to dry eye-like symptoms. Specifically there was an increase in the number of cell layers lining each acinus, fewer and more condensed lipid droplets, “swollen” eyelids, increased protein concentration in the tears and increased lymphangiogenesis. Inhibition of the notch signaling pathway using dnMAML mice resulted in a significant meibomian gland defect. With a phenotype similar to what was seen in the absence of PPARλ. Loss of Jag1 did not have as profound of an effect on meibomian gland formation or function, which may be explained by compensation by other Notch ligands.
Together these data, suggest that PPARλ is critical for the proper formation and function of the meibomian glands and also demonstrate a mouse model that can be used to study MGD. Notch signaling also appears to be an important regulator of PPARλ.
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