Corneal nerve dysfunction is the pathophysiologic basis of many ocular surface diseases, causing considerable morbidity, including neurotrophic keratitis and dry eye disease and therefore corneal nerve health is a prerequisite for the maintenance of vision. Despite the traditional point of view that immune cells are deleterious for nerve regeneration, recent evidence suggests that immune cells can show beneficial effects in neuronal regeneration. For instance, macrophages and conventional dendritic cells are among the key players in providing a neuro-protective and neuro-trophic microenvironment for nerve regeneration following nerve damage. Despite recent evidence on neuro-protective and neuro-regenerative functions of immune cells, the role and source of endogenous neurotrophic molecules in the cornea remains elusive. Moreover, the impact of recently identified plasmacytoid dendritic cells (pDCs), a vital subset of immune cells that reside in the anterior stroma just beneath sub-basal corneal nerve plexus of cornea, remains to be determined. These cells orchestrate and link innate and adaptive immune responses and are implicated in the induction of tolerance to transplanted tissues or tumors. Our preliminary results suggest that pDCs are vital in the maintenance and function of corneal nerves, as we demonstrate that local depletion of pDCs in the cornea leads to abrupt and severe nerve loss and diminishment of corneal sensation. Our hypothesis is that pDCs contribute to maintenance, function, and regeneration of nerves through secretion of neurotrophic molecules.
Our specific aims i nclude evaluating the significance of pDCs on corneal nerve maintenance and health as well as studying the impact of pDCs on neural regeneration in the cornea following nerve damage. Our fresh perspective on how pDCs contribute to regulation of corneal nerve microenvironment holds promise of amplifying our knowledge far beyond the current state on the cross talk between nerve fibers and immune cells in the cornea and the impact of such cross talk on corneal nerve health and function. Furthermore, this application suggests in vivo approaches for assessing significance of corneal pDCs, in nerve protection and regeneration. Therefore, this proposal will elucidate the neuro-protective and neuro-regenerative properties of pDCs, may result in novel therapeutic approaches, and is potentially applicable in tissues other than cornea and conditions in which neuro-regeneration is vital, including traumatic nervous system injuries, neurodegenerative diseases, and peripheral neuropathies.

Public Health Relevance

Identification and understanding of critical pathways mediating corneal nerve maintenance, health, and regeneration is crucial to treat and prevent potentially blinding and debilitating diseases associated with corneal nerve loss. This proposal will investigate a new role for a plasmacytoid dendritic cells, a unique subset of bone marrow-derived cells, identified in the cornea by us, in the maintenance of corneal nerve health and thus in preservation of vision. Our proposal may result in the development of novel drugs for the treatment of pathological eye conditions including neurotrophic keratitis and dry eye disease.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21EY025393-02
Application #
9208776
Study Section
Diseases and Pathophysiology of the Visual System Study Section (DPVS)
Program Officer
Mckie, George Ann
Project Start
2016-02-01
Project End
2018-01-31
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
2
Fiscal Year
2017
Total Cost
$185,625
Indirect Cost
$73,125
Name
Tufts University
Department
Type
Independent Hospitals
DUNS #
079532263
City
Boston
State
MA
Country
United States
Zip Code
02111
Morkin, Melina I; Hamrah, Pedram (2018) Efficacy of self-retained cryopreserved amniotic membrane for treatment of neuropathic corneal pain. Ocul Surf 16:132-138
Cavalcanti, Bernardo M; Cruzat, Andrea; Sahin, Afsun et al. (2018) In vivo confocal microscopy detects bilateral changes of corneal immune cells and nerves in unilateral herpes zoster ophthalmicus. Ocul Surf 16:101-111
Moein, Hamid-Reza; Kheirkhah, Ahmad; Muller, Rodrigo T et al. (2018) Corneal nerve regeneration after herpes simplex keratitis: A longitudinal in vivo confocal microscopy study. Ocul Surf 16:218-225
Lopez, Maria J; Seyed-Razavi, Yashar; Jamali, Arsia et al. (2018) The Chemokine Receptor CXCR4 Mediates Recruitment of CD11c+ Conventional Dendritic Cells Into the Inflamed Murine Cornea. Invest Ophthalmol Vis Sci 59:5671-5681
Mikolajczak, Janine; Zimmermann, Hanna; Kheirkhah, Ahmad et al. (2017) Patients with multiple sclerosis demonstrate reduced subbasal corneal nerve fibre density. Mult Scler 23:1847-1853
Dieckmann, Gabriela; Goyal, Sunali; Hamrah, Pedram (2017) Neuropathic Corneal Pain: Approaches for Management. Ophthalmology 124:S34-S47
Hamrah, Pedram; Sahin, Afsun; Oaklander, Anne Louise (2017) Widespread effects of clinically unilateral focal nerve injuries. Pain 158:1175-1176
Cruzat, Andrea; Qazi, Yureeda; Hamrah, Pedram (2017) In Vivo Confocal Microscopy of Corneal Nerves in Health and Disease. Ocul Surf 15:15-47
Hamrah, Pedram; Seyed-Razavi, Yashar; Yamaguchi, Takefumi (2016) Translational Immunoimaging and Neuroimaging Demonstrate Corneal Neuroimmune Crosstalk. Cornea 35 Suppl 1:S20-S24
Yamaguchi, Takefumi; Hamrah, Pedram; Shimazaki, Jun (2016) Bilateral Alterations in Corneal Nerves, Dendritic Cells, and Tear Cytokine Levels in Ocular Surface Disease. Cornea 35 Suppl 1:S65-S70

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