Inflammatory diseases of the lacrimal gland such as Sj?gren's syndrome, sarcoidosis, and chronic graft versus-host disease or simply as occurs with advanced age, lead to inadequate secretion of the aqueous layer of the tear film, which is a leading cause of keratoconjunctivitis sicca (KCS) or dry eye syndromes. Common denominators for these diseases are the phenotypic signs of chronic inflammation (injury) of the lacrimal gland with loss of parenchymal tissue (the tear secreting acinar and ductal epithelial cells) and the inability of the gland to repair itself. To date there are no cures for dry eye syndromes. We recently discovered that the lacrimal gland contains label retaining slow cycling progenitor cells that are involved in repair following experimentally induced injury. We also discovered that during the repair phase, cells with a mesenchymal stem cell (MSC) phenotype are generated through induction of epithelial-to-mesenchymal transition (EMT). MSCs actively participate in lacrimal gland repair to generate acinar and ductal epithelial cells and restore adequate tear production. In the present proposal, we are capitalizing on these discoveries by hypothesizing that: 1) lacrimal gland repair mechanisms are compromised in animal models of autoimmune-driven lacrimal gland deficiencies largely because their extracellular matrix is disrupted, 2) manipulation of matrix metalloproteinases (MMPs), especially MMP2 and/or 9 expression/activity may improve lacrimal gland regeneration, and 3) that delivery of exogenous stem cells will accelerate the healing process of inflamed lacrimal glands. To test these hypotheses, we propose the following specific aims: 1-Iinvestigate changes in the extracellular matrix, cell adhesion molecules and matrix modifying enzymes in chronically inflamed lacrimal glands;2-Test the hypothesis that manipulation of MMP2 and 9 expression and/or activity would improve healing of chronically inflamed lacrimal glands;3-To use genetic cell lineage tracing to further characterize the phenotype of the cells involved in initiation of EMT and mesenchymal-epithelial transition (MET) during experimentally induced injury to the lacrimal gland;and 4-Test the potential of cultured MSCs to accelerate repair of diseased lacrimal glands when delivered in vivo to animal models of autoimmune lacrimal gland deficiency. There are currently no cures for severe dry eye resulting from loss of the moisture producing cells of the lacrimal glands. The studies described here, if successful, will lead to new strategies to halt, and maybe reverse, the loss of these cells which will restore normal tear production and alleviate the ocular surface discomfort associated with dry eye syndromes.

Public Health Relevance

There are currently no cures for dry eye diseases resulting from loss of the moisture producing cells of the lacrimal glands. We discovered that the murine lacrimal gland can repair itself following injury by mobilizing mesenchymal stem cells (MSC). The overall goal of this proposal is to understand why the repair mechanisms are compromised in diseased lacrimal glands and if MSC therapy is a viable option. The knowledge gained will unravel new strategies to promote regeneration of chronically inflamed human lacrimal glands that would restore adequate aqueous tear production.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY012383-12
Application #
8721960
Study Section
(DPVS)
Program Officer
Mckie, George Ann
Project Start
1999-01-01
Project End
2016-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
12
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Tufts University
Department
Type
Schools of Dentistry/Oral Hygn
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02111
Hawley, Dillon; Ding, Jian; Thotakura, Suharika et al. (2017) RNA-Seq and CyTOF immuno-profiling of regenerating lacrimal glands identifies a novel subset of cells expressing muscle-related proteins. PLoS One 12:e0179385
Basova, Liana V; Tang, Xin; Umasume, Takeshi et al. (2017) Manipulation of Panx1 Activity Increases the Engraftment of Transplanted Lacrimal Gland Epithelial Progenitor Cells. Invest Ophthalmol Vis Sci 58:5654-5665
Bron, Anthony J; de Paiva, Cintia S; Chauhan, Sunil K et al. (2017) TFOS DEWS II pathophysiology report. Ocul Surf 15:438-510
Hawley, Dillon; Aluri, Hema; Armaos, Helene et al. (2016) Human postmortem lacrimal and submandibular glands stored in RNAlater are suitable for molecular, biochemical, and cell biological studies. Mol Vis 22:1221-1228
Bykhovskaya, Yelena; Gromova, Anastasia; Makarenkova, Helen P et al. (2016) Abnormal regulation of extracellular matrix and adhesion molecules in corneas of patients with keratoconus. Int J Keratoconus Ectatic Corneal Dis 5:63-70
Aluri, Hema S; Kublin, Claire L; Thotakura, Suharika et al. (2015) Role of Matrix Metalloproteinases 2 and 9 in Lacrimal Gland Disease in Animal Models of Sjögren's Syndrome. Invest Ophthalmol Vis Sci 56:5218-28
Umazume, Takeshi; Thomas, William M; Campbell, Sabrina et al. (2015) Lacrimal Gland Inflammation Deregulates Extracellular Matrix Remodeling and Alters Molecular Signature of Epithelial Stem/Progenitor Cells. Invest Ophthalmol Vis Sci 56:8392-402
Makarenkova, Helen P; Dartt, Darlene A (2015) Myoepithelial Cells: Their Origin and Function in Lacrimal Gland Morphogenesis, Homeostasis, and Repair. Curr Mol Biol Rep 1:115-123
Voronov, Dmitry; Gromova, Anastasia; Liu, Daren et al. (2013) Transcription factors Runx1 to 3 are expressed in the lacrimal gland epithelium and are involved in regulation of gland morphogenesis and regeneration. Invest Ophthalmol Vis Sci 54:3115-25
You, Samantha; Avidan, Orna; Tariq, Ayesha et al. (2012) Role of epithelial-mesenchymal transition in repair of the lacrimal gland after experimentally induced injury. Invest Ophthalmol Vis Sci 53:126-35

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