Thursday, April 25, 2024
4/25/2024
The lacrimal gland (LG) produces fluid and proteins essential for ocular surface function. A subset of severe dry eye disease (DED) cases are associated with Sjögren’s syndrome (SS), an autoimmune disease associated with exocrinopathy and systemic inflammation. SS-associated DED is characterized by severe LG inflammation (dacryoadenitis) and reduced tear secretion, with tears containing an altered spectrum of proteins which may provoke ocular surface inflammation. In the male NOD mouse, a model of ocular symptoms of SS, expression and activity of cathepsin S (CTSS) is highly increased in LG and in tears in parallel with disease; increased tear CTSS is also seen in SS patients. Treatment of male NOD mice with a CTSS inhibitor suppressed ocular symptoms of SS. A complication of the use of CTSS inhibitors reported so far in clinical trials is the induction of additional CTSS expression, suggesting a feedback loop responsible for the regulation of the expression and activity of this enzyme which is so critical in inflammatory processes. An alternative to CTSS inhibition for treatment of ocular symptoms of SS is identification and reversal of processes in the LG driving its: 1)increased expression; 2) increased tear secretion; and 3)participation in LG inflammation. Three Aims are proposed: Aim 1. Does dysregulation of PP2A signaling contribute to increased CTSS in LGAC in SS? Protein phosphatase 2A (PP2A) regulates CTSS mRNA stability/translation through dephosphorylation of tristetraprolin (TTP). Mechanisms of dysregulation of PP2A-TTP leading to increased CTSS expression and secretion from LGAC will be explored in NOD and control mice, and in cultured LG acinar cells (LGAC). The efficacy of the PP2A activator, DT-061, on LG and ocular surface disease will be determined in NOD and control mice. Aim 2. Does increased trafficking through the minor secretory pathway promote increased tear CTSS in SS? Most tear proteins are secreted from the LGAC “major” secretory pathway, but a “minor” pathway from endolysosomes may contribute CTSS to tears. In Rab deficient mice with altered tear contributions from major and minor pathways, changes in minor pathway cargo in tears beyond CTSS will be identified. Correlative light and electron microscopy will identify endolysosomal membranes responsible for minor pathway secretion; these new measures will be applied to test whether the minor pathway is increased in SS using NOD and control mice. Aim 3. Does local or systemic modulation of endolysosomal traffic through PIKFYVE inhibition suppress CTSS-mediated pathology in SS? PIKFYVE is a master regulator of endolysosomal trafficking and maturation, regulating CTSS function in antigen presentation and expression of IL12/23. The effects of local and systemic inhibition of PIKFYVE on ocular symptoms of SS will be evaluated in NOD and control mice, in parallel with additional indicators of LGAC autoimmune epithelitis, tear and exosome abundance, and expression of IL-12/23. Results from these studies will collectively define changes in secretory pathways that may contribute to ocular manifestations of SS, while identifying new therapeutic agents yet unexplored in SS to mitigate ocular disease.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
