My ultimate goal for the mentored clinical scientist development award is to acquire expertise in the field of innate immunity. Specifically, I will investigate the role of Fas Ligand (FasL) in regulating neutrophil-mediated (innate immunity) inflammation in the cornea. The combination of this training with my previous research experience in adaptive immunity will give me the opportunity to develop a comprehensive research program to study corneal immunology. The Cole Eye Institute and the Immunology Department at the Cleveland Clinic Foundation provide the clinical and basic science support necessary to allow the development of clinical scientists and the unique opportunity to practice translational medicine. Overall, the training environment, at this institution will provide me with both the technical and intellectual tools necessary to become a successful investigator in vision research. My long-term career goal is to establish a comprehensive and independent research program dedicated to dissect the regulatory immune mechanism used by the cornea to control inflammation. Scientific findings generated form this research will be used to development target-specific immunotherapies for the treatment of destructive inflammatory diseases of the cornea. The objective of this project is to test the novel hypothesis that the forms of FasL expressed in the cornea are a key factor in the differential regulation of inflammation: soluble FasL blocks and membrane FasL induces keratitis. Preliminary data demonstrate that soluble FasL is anti-inflammatory by inhibiting neutrophil activation, while membrane FasL activates them and is pro-inflammatory. The proposed studies will implement a novel method of in vivo transfection of corneal stromal cells using adenoviral vectors to express soluble and membrane FasL in the cornea and determine the biological regulation of neutrophil activation in corneal tissue. In vitro experiments using isolated neutrophils and cells lines transfected with membrane and soluble FasL will complement these studies and will facilitate the dissection of cellular and molecular signals differentially regulated by these molecules. Moreover, we will use the in vivo transfection technique to determine the role of soluble Fas L in the down-regulation and prevention of neutrophil-mediated ocular damage in a model of lipopolysaccharide induced keratitis that has clinical implications. We anticipate that these studies will yield new information about the regulation of ocular inflammation by FasL and lead to the development of new treatments using soluble FasL to treat and prevent neutrophil-mediated ocular damage.

National Institute of Health (NIH)
National Eye Institute (NEI)
Clinical Investigator Award (CIA) (K08)
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Special Emphasis Panel (ZEY1-VSN (04))
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Shen, Grace L
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Cleveland Clinic Lerner
Other Basic Sciences
Schools of Medicine
United States
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Tan, Yaohong; Cruz-Guilloty, Fernando; Medina-Mendez, Carlos A et al. (2012) Immunological disruption of antiangiogenic signals by recruited allospecific T cells leads to corneal allograft rejection. J Immunol 188:5962-9
Carlson, Eric C; Sun, Yan; Auletta, Jeffery et al. (2010) Regulation of corneal inflammation by neutrophil-dependent cleavage of keratan sulfate proteoglycans as a model for breakdown of the chemokine gradient. J Leukoc Biol 88:517-22
Hollyfield, Joe G; Perez, Victor L; Salomon, Robert G (2010) A hapten generated from an oxidation fragment of docosahexaenoic acid is sufficient to initiate age-related macular degeneration. Mol Neurobiol 41:290-8
Chinnery, Holly R; Carlson, Eric C; Sun, Yan et al. (2009) Bone marrow chimeras and c-fms conditional ablation (Mafia) mice reveal an essential role for resident myeloid cells in lipopolysaccharide/TLR4-induced corneal inflammation. J Immunol 182:2738-44
Hollyfield, Joe G; Bonilha, Vera L; Rayborn, Mary E et al. (2008) Oxidative damage-induced inflammation initiates age-related macular degeneration. Nat Med 14:194-8
Amescua, Guillermo; Collings, Fitz; Sidani, Amer et al. (2008) Effect of CXCL-1/KC production in high risk vascularized corneal allografts on T cell recruitment and graft rejection. Transplantation 85:615-25
Ide, Takeshi; Yoo, Sonia H; Kymionis, George D et al. (2008) Descemet-stripping automated endothelial keratoplasty: effect of anterior lamellar corneal tissue-on/-off storage condition on Descemet-stripping automated endothelial keratoplasty donor tissue. Cornea 27:754-7
Carlson, Eric C; Lin, Michelle; Liu, Chia-Yang et al. (2007) Keratocan and lumican regulate neutrophil infiltration and corneal clarity in lipopolysaccharide-induced keratitis by direct interaction with CXCL1. J Biol Chem 282:35502-9
Carlson, Eric C; Drazba, Judith; Yang, Xiaping et al. (2006) Visualization and characterization of inflammatory cell recruitment and migration through the corneal stroma in endotoxin-induced keratitis. Invest Ophthalmol Vis Sci 47:241-8
Carlson, Eric C; Liu, Chia-Yang; Yang, Xiaoping et al. (2004) In vivo gene delivery and visualization of corneal stromal cells using an adenoviral vector and keratocyte-specific promoter. Invest Ophthalmol Vis Sci 45:2194-200