Thrombospondin (TSP-1) is essential for maintaining ocular immune privilege and preventing potentially blinding effects of ocular inflammation. An extracellular matrix protein TSP-1 is synthesized by several ocular epithelia as well as resident antigen presenting cells (APCs), which contribute to the immune privilege status of the eye. The anti-inflammatory effects of TSP-1 in ocular inflammation are apparent from the spontaneous development of chronic ocular surface inflammation in TSP-1 deficient mice. The studies described in this proposal seek to elucidate immunologic mechanisms underlying such inflammatory responses noted in the absence of TSP-1. The first specific aim seeks to determine the significance of thrombospondin-1 (TSP-1) in the prevention of ocular inflammation. Experiments in this aim will allow us to characterize immune effectors developed in the absence of TSP-1 that lead to ocular surface inflammation.
The second aim seeks to investigate the specific contribution of local TSP-1 in the lacrimal glands towards altering immune effectors. Considering the multidomain structure of a large molecule like TSP-1 with multiple cell type specific biological effects, these investigations will clarify mechanisms by which TSP-1 contributes to the prevention of chronic ocular inflammation. Since TSP-1 is known to be important in maintaining immune privilege these studies can build further on the existing knowledge of ocular immune responses and provide insights into novel potential therapeutic strategies.

Public Health Relevance

Immune privilege of the eye is an evolutionary phenomenon that protects the eye from potential vision-compromising inflammatory immune response. Understanding immunologic mechanisms underlying this phenomenon can help improve current therapeutic approaches used to treat ocular inflammation. The long-term goal of these investigations is to develop novel anti-inflammatory therapeutic strategies to counter inflammatory conditions such as autoimmune diseases and transplant rejections.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Anterior Eye Disease Study Section (AED)
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Shen, Grace L
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Schepens Eye Research Institute
United States
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Contreras Ruiz, L; Mir, F A; Turpie, B et al. (2017) Thrombospondin-derived peptide attenuates Sjögren's syndrome-associated ocular surface inflammation in mice. Clin Exp Immunol 188:86-95
Contreras-Ruiz, Laura; Mir, Fayaz A; Turpie, Bruce et al. (2016) Sjögren's syndrome associated dry eye in a mouse model is ameliorated by topical application of integrin ?4 antagonist GW559090. Exp Eye Res 143:1-8
Shatos, Marie A; Hodges, Robin R; Morinaga, Masahiro et al. (2016) Alteration in cellular turnover and progenitor cell population in lacrimal glands from thrombospondin 1-/- mice, a model of dry eye. Exp Eye Res 153:27-41
Contreras-Ruiz, Laura; Masli, Sharmila (2015) Immunomodulatory cross-talk between conjunctival goblet cells and dendritic cells. PLoS One 10:e0120284
Mir, Fayaz Ahmad; Contreras-Ruiz, Laura; Masli, Sharmila (2015) Thrombospondin-1-dependent immune regulation by transforming growth factor-?2-exposed antigen-presenting cells. Immunology 146:547-56
Regenfuß, Birgit; Dreisow, Marie-Luise; Hos, Deniz et al. (2015) The Naïve Murine Cornea as a Model System to Identify Novel Endogenous Regulators of Lymphangiogenesis: TRAIL and rtPA. Lymphat Res Biol 13:76-84
Masli, Sharmila (2015) Matricellular Proteins in Ocular Diseases. J Ocul Pharmacol Ther 31:365
Terzulli, Marielle; Contreras-Ruiz, Laura; Ruiz, Laura Contreras et al. (2015) TSP-1 Deficiency Alters Ocular Microbiota: Implications for Sjögren's Syndrome Pathogenesis. J Ocul Pharmacol Ther 31:413-8
Contreras-Ruiz, Laura; Ryan, Denise S; Sia, Rose K et al. (2014) Polymorphism in THBS1 gene is associated with post-refractive surgery chronic ocular surface inflammation. Ophthalmology 121:1389-97
Dartt, Darlene A; Masli, Sharmila (2014) Conjunctival epithelial and goblet cell function in chronic inflammation and ocular allergic inflammation. Curr Opin Allergy Clin Immunol 14:464-70

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