Aqueous-deficient dry eye (ADDE) is among the most common and debilitating clinical manifestations of systemic autoimmune diseases such as Sjgren's syndrome (SS) for which there is no cure. While it is well established that chronic inflammation represents a predominant driving force in ADDE, an important yet often overlooked component of ADDE is altered innervation of the cornea and lacrimal gland. Loss of neuronal inputs upsets the complex reflex network connecting the ocular mucosal tissues (e.g. cornea, limbus, conjunctiva) and the tear secreting machinery (e.g. lacrimal glands) that maintains ocular surface and glandular epithelial homeostasis. Yet, despite the essential need for a functional nerve supply, current medications and therapeutic strategies do not address the importance of maintaining and/or reinnervating ocular tissues. As such, it is essential to identify new therapies that possess neuroregenerative and pro- secretory properties to restore ocular health in ADDE. In this proposal we define the impact of a novel therapeutic, lacripep, on maintaining/promoting functional innervation of the cornea and lacrimal gland. Lacripep is the active component of lacritin, a naturally occurring glycoprotein in human tears with prosecretory and mitogenic properties. Recently, we reported reduced levels of lacritin in the tears of human patients with SS and discovered that topical application of lacritin promoted tear secretion, improved corneal epithelial integrity and reduced inflammation in an autoimmune-regulator (Aire)-deficient mouse model of SS-associated ADDE. In our preliminary studies using this model we show lacripep not only promotes tear production but also rescues innervation of the cornea and lacrimal glands, thus restoring an essential component of ocular homeostasis. Based on these studies, we propose to determine the impact of lacripep on corneal and lacrimal gland innervation during ADDE development, as well as defining mechanisms by which lacripep maintains and/or restores innervation. Thus, the goals of this proposal are to:
Aim 1) Define the neuroregenerative potential of lacripep in the cornea and lacrimal gland during dry eye disease progression;
Aim 2) Define the mechanisms by which lacripep achieves functional innervation of the cornea during the development of dry eye;
and Aim 3) Determine if lacripep restores tear secretion by preferentially increasing functional parasympathetic innervation of the lacrimal gland. Using a combination of imaging, biochemical and genetic approaches, the proposed studies will considerably advance our understanding of the mechanisms by which loss of corneal innervation and secretory function occurs as well as the functional significance of denervation on disease progression. With 95% of dry eye patients selectively deficient in lacritin, topical use of lacripep as a natural replacement therapy for dry eye presents a tremendous opportunity to fill an enormous void in the clinical management of these patients.

Public Health Relevance

Autoimmune diseases like Sjgren's syndrome cause a severe, aqueous-deficient dry eye (ADDE) that is highly recalcitrant to treatment. Reduced sensory innervation of the cornea in patients with ADDE is thought to perpetuate the disease, as sensory nerves are essential for maintaining ocular health and stimulating tear secretion. Despite the significant connection between nerve loss and ocular surface disease in the pathogenesis of ADDE, current medications and therapeutic strategies do not address the need to maintain and/or reinnervate ocular tissues, as well as stimulate tear secretion. In this proposal we will define the molecular events leading to nerve loss in ADDE, as well as determine the neuroregenerative potential of lacripep, a novel therapeutic for restoring/maintaining innervation and tear secretion in dry eye. Our findings will have significant implications for the millions of patients who suffer from ADDE, as well as many other diseases of the ocular surface that lead to, or result from, loss of corneal innervation.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY025980-02
Application #
9113006
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mckie, George Ann
Project Start
2015-08-01
Project End
2020-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Anatomy/Cell Biology
Type
Schools of Dentistry/Oral Hygn
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118
McNamara, Nancy A; Ge, Shaokui; Lee, Salena M et al. (2016) Reduced Levels of Tear Lacritin Are Associated With Corneal Neuropathy in Patients With the Ocular Component of Sjögren's Syndrome. Invest Ophthalmol Vis Sci 57:5237-5243