Aqueous-deficient dry eye is among the most common and debilitating clinical manifestations of systemic autoimmune diseases such as Sjgren's syndrome. It is well established that chronic inflammation represents the predominant driving force in dry eye disease, however, the causal mechanisms underlying disease initiation and progression are unclear. As such, there is no cure for dry eye and few treatment options are available for sufferers. A long overlooked component of aqueous-deficient dry eye in autoimmune diseases like SS, is disruption of the complex reflex network of corneal nerves that connect the sensory tissues with the secretory glands. The integrity of this neural network is essential for maintaining a healthy ocular surface and there is growing evidence that innervation itself is a negative modulator of inflammation. In this application we will use a mouse model of Sjgren's syndrome to define the cellular processes that lead to denervation of the cornea and lacrimal gland in dry eye, as well as identify mechanisms to restore innervation and reverse ocular surface damage in Sjgren's syndrome patients. We hypothesize that chronic, T cell-mediated inflammation alters innervation by inhibiting epithelial maintenance of nerves in the cornea and lacrimal gland, resulting in loss of tissue integrity and reduced tear secretion that perpetuate ocular surface disease and aqueous tear deficiency. To test this hypothesis we will: 1) Define the timing of denervation and corresponding pathological changes in the cornea, lacrimal gland and associated nerves during dry eye development; and 2) Determine the mechanisms by which T cell-mediated inflammation alters innervation of the cornea and lacrimal glands. To achieve these aims we will employ a combination of in vivo and ex vivo studies, as well as transcriptional profiling, in a well-characterized mouse model of Sjgren's syndrome. Outcomes here will define modulators of ocular organ innervation, identify potential biomarkers of disease progression, and reveal novel regenerative strategies for reversing dry eye disease.
Aqueous-deficient dry eye in Sjgren's syndrome is highly recalcitrant to existing therapies. Neurological manifestations of Sjgren's syndrome but how chronic inflammation affects the have long been recognized, complex neural network that connects the ocular surface with the tear-secreting machinery of the lacrimal gland has not been defined. Here, we will determine the cellular processes that link chronic inflammation in Sjgren's syndrome to nerve loss in the cornea and lacrimal gland. Knowledge gained will be critical for achieving our long-term goal of developing mechanism-based, regenerative therapeutics for dry eye patients.
| Farmer, D'Juan T; Nathan, Sara; Finley, Jennifer K et al. (2017) Defining epithelial cell dynamics and lineage relationships in the developing lacrimal gland. Development 144:2517-2528 |
| Chen, Feeling Y; Lee, Albert; Ge, Shaokui et al. (2017) Aire-deficient mice provide a model of corneal and lacrimal gland neuropathy in Sjögren's syndrome. PLoS One 12:e0184916 |
