Dry eye is a common problem with a severe impact on the quality of life and potential vision-threatening complications. It often results from lacrimal insufficiency caused by immune-related processes, as in Sjogren's syndrome, or by hormone changes associated with aging and various physiological states. One critical hormonal influence on the lacrimal glands appears to be prolactin. Studies with human subjects, hypophysectomized rats, transgenic mice, and acinar cells in primary culture indicate that prolactin can impair lacrimal function, even at serum concentrations within the range of normal values. Moreover, the source of the prolactin that impairs lacrimal gland function may be the lacrimal glands themselves. The lacrimal glands express prolactin mRNA and protein, which may act as an autocrine or intracrine factor that in some circumstances may interfere with secretion. This project will use lacrimal acinar cells in primary culture to answer the following questions: 1. Does locally expressed prolactin act as an autocrine/intracrine factor that supports secretory functions at normal concentrations and impairs them at excessive concentrations? Neutralizing antibodies and antisense reagents will be used to minimize actions of locally expressed prolactin. Expression constructs will be used to overexpress prolactin. Acinar cell morphology, carbachol-induced protein secretion, expression of polymeric immunoglobulin receptors, and expression of ion transport proteins will be evaluated for changes related to altered prolactin expression. 2. Do altered forms of prolactin (16 kDa and phosphorylated 24 kDa) that have inhibitory effects in other cells inhibit lacrimal secretory function? The effects of overexpressed and added forms will be tested as in Specific Aim 1. 3. Does lacrimal prolactin act as a paracrine factor contributing to autoimmune activation? Antisense reagents and expression constructs will be used to suppress or enhance acinar cell prolactin expression, and the modified cells will be tested for their ability to promote proliferation of autologous lymphocytes in mixed cell reactions. This work will advance our understanding of significant mechanisms in lacrimal physiology, and it will have immediate implications for the direction of other studies now in progress. It also has the possibility of stimulating much work well beyond its present scope, including epidemiological studies aimed at identifying sub-populations of lacrimal deficiency patients with different etiologies, followed by design of appropriate, highly specific therapies.
