Adequate production of saliva is essential for oral health and general well-being. This is best appreciated under conditions of salivary gland hypofunction. Dry mouth (xerostomia) is associated with significant morbidity as individuals experience an altered perception of taste, problems swallowing and speaking and an increased susceptibility to oral infections and dental caries. A major cause of dry mouth is the relatively common autoimmune disease, Sjgrens syndrome (SS). SS has a high female predominance and is associated with profound loss of salivary flow with few treatment options. Notably, while late in the disease when the loss of fluid flow can be attributed to glandular destruction following lymphocyte infiltration, patients often present with a marked loss of salivary gland function, but without extensive lymphocyte involvement and with seemingly intact glandular structure. This information suggests strongly that an early event in SS is disruption to the cellular machinery which produces saliva. Consistent with this idea, we have recently reported that the abundance of the intracellular Ca2+ release channel, the inositol 1,4,5-trisphosphate receptor (IP3R), which is central to the mechanisms responsible for ion and fluid movement in salivary glands, is reduced in both mouse models and SS patients with low grade lymphocyte involvement and intact glandular structure. Furthermore, we now shown that prior to down-regulation of the full-length protein that the IP3R is subject to limited proteolytic cleavage. Surprisingly, proteolytic cleavage does not disable the channel but markedly alters the spatiotemporal properties of the Ca2+ signal. The central scientific premise driving this proposal is that IP3R play pivotal roles in the loss of fluid secretion in SS. Experiments are designed to explore in mechanistic detail the hypothesis that first, the altered Ca2+ signal following IP3R proteolysis results in inappropriate activation of Ca2+ dependent effectors necessary for fluid secretion and homeostasis and subsequently how IP3R are downregulated ultimately resulting in long term hypofunction. We propose to use several complementary models of SS, including the Aec1Aec2 NOD and IL14? mice, together with mouse models where SS disease is induced by acutely activating the immune system. We plan to confirm major findings using patient derived tissue. To address these goals, the specific aims will first investigate the mechanisms underlying IP3R fragmentation and its impact on the spatiotemporal properties of Ca2+ signaling in salivary glands at various stages early in disease (Aim1). The consequences of the altered Ca2+ signals for both the acute activation of Cl and K channels and mitochondrial bioenergetics necessary to maintain homeostasis.
(Aim 2). Finally, we will explore the contribution of downregulation and altered transcription for the reduction of IP3R protein levels. The overarching objective of this project is to gain a mechanistic understanding of processes occurring early in SS, with a view that this knowledge may ultimately suggest novel therapeutic targets for the treatment of disease.
Sjgrens syndrome (SS) is a relatively common autoimmune disease which results in dry mouth and dry eyes because of failure of the body to make saliva and tears. Initially, the lack of fluid is because of disruption to the inositol 1,4,5-trisphosphate receptor calcium release channel (IP3R), a key component of the cellular machinery which makes saliva, rather than the gland being destroyed by the immune system. This proposal is designed to comprehensively investigate how the function of IP3R is altered in SS and how these events contribute to disease progression with a view that this knowledge may ultimately lead to novel therapeutic targets for treatment.
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