Lymphatic research represents an explosive field of new discovery in recent years. The cornea provides an ideal tissue for lymphatic studies due to its accessible location, transparent nature, and lymphatic-free and - inducible features. Additionally, corneal transplantation offers an excellent model for lymphatic research because it allows for (i) functional lymphatic cell trafficking studies;and (ii) the identification of cellulr contributions (donor or recipient source) to the process of lymphangiogenesis (LG). Studies on corneal LG bears direct implication to high-risk (HR) transplantation where grafting is performed on lymphatic-rich host beds and the rejection rate can be as high as 90%. Many patients who are blind from corneal diseases fall into this category after inflammatory, infectious, traumatic, r chemical insults. To date, there is no effective management for this situation. Our long-term goal is to elucidate the molecular and cellular mechanisms of LG using both in vitro cell culture and in vivo corneal models, a necessary prerequisite to the development of new therapeutic protocols. Our hypothesis is that corneal LG can be manipulated through specific lymphatic factors or cell populations. Molecular blockade of the lymphatic factors promotes HR graft survival. This proposal is based on the most recent advances in technology and lymphatic research, and a large amount of preliminary data we have generated during the past few years.
The specific aims are: 1) define the role of integrin alpha 9 (Itga-9) in corneal lymphatic valve formation and function using neutralizing antibodies and knockout mice;2) determine the role of Angiopoietin-2 (Ang-2) in lymphatic endothelial cell functions in vitro, and LG and transplant rejection in vivo using small interference RNAs, neutralizing antibodies, and knockout mice;and 3) investigate the cell origins of lymphatic vessels using cell type-specific gene-manipulated mice and live imaging techniques. Research on corneal LG will have broader clinical implications beyond the treatment of ocular diseases alone since lymphatic dysfunction is associated with a diverse array of diseases and conditions, which include but are not limited to cancer metastasis, inflammation, infections, diabetes, obesity, hypertension and lymphedema.

Public Health Relevance

Lymphatic vessel formation accompanies many corneal diseases after an inflammatory, infectious, traumatic, or chemical insult. It is also a primary mediator of transplant rejection, which can be as high as 90%, irrespective of current treatment modalities. This project will provide novel insights into the mechanisms of lymphatic growth and offer new therapeutic strategies for corneal transplant rejection, and potentially other lymphatic disorders in the body ranging from cancer metastasis to diabetes and lymphedema.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Anterior Eye Disease Study Section (AED)
Program Officer
Mckie, George Ann
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University of California Berkeley
Schools of Optometry/Ophthalmol
United States
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Zhang, Liwei; Li, Guangyu; Sessa, Roberto et al. (2017) Angiopoietin-2 Blockade Promotes Survival of Corneal Transplants. Invest Ophthalmol Vis Sci 58:79-86
Kang, Gyeong Jin; Truong, Tan; Huang, Eric et al. (2016) Integrin Alpha 9 Blockade Suppresses Lymphatic Valve Formation and Promotes Transplant Survival. Invest Ophthalmol Vis Sci 57:5935-5939
Sessa, Roberto; Yuen, Don; Wan, Stephanie et al. (2016) Monocyte-derived Wnt5a regulates inflammatory lymphangiogenesis. Cell Res 26:262-5
Kang, Gyeong Jin; Ecoiffier, Tatiana; Truong, Tan et al. (2016) Intravital Imaging Reveals Dynamics of Lymphangiogenesis and Valvulogenesis. Sci Rep 6:19459
Grimaldo, Sammy; Yuen, Don; Theis, Jaci et al. (2015) MicroRNA-184 Regulates Corneal Lymphangiogenesis. Invest Ophthalmol Vis Sci 56:7209-13
Heindl, Ludwig M; Kaser-Eichberger, Alexandra; Schlereth, Simona L et al. (2015) Sufficient Evidence for Lymphatics in the Developing and Adult Human Choroid? Invest Ophthalmol Vis Sci 56:6709-10
Altiok, Eda; Ecoiffier, Tatiana; Sessa, Roberto et al. (2015) Integrin Alpha-9 Mediates Lymphatic Valve Formation in Corneal Lymphangiogenesis. Invest Ophthalmol Vis Sci 56:6313-9
Schroedl, Falk; Kaser-Eichberger, Alexandra; Schlereth, Simona L et al. (2014) Consensus statement on the immunohistochemical detection of ocular lymphatic vessels. Invest Ophthalmol Vis Sci 55:6440-2
Truong, Tan; Huang, Eric; Yuen, Don et al. (2014) Corneal lymphatic valve formation in relation to lymphangiogenesis. Invest Ophthalmol Vis Sci 55:1876-83
Yuen, D; Leu, R; Tse, J et al. (2014) Novel characterization of bEnd.3 cells that express lymphatic vessel endothelial hyaluronan receptor-1. Lymphology 47:73-81

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