Lymphatic research denotes an explosive field of new discovery and lymphatic dysfunction has been found in myriad of diseases. To date, there is still a significant lack of effective treatments for lymphatic diseases in general. The cornea offers an ideal site for lymphatic research due to its accessible location, transparent nature, and lymphatic-free and -inducible features. It is also found that corneal lymphatic vessels develop luminal valves as lymphangiogenesis (LG) proceeds. Studies on corneal LG bears direct implications to transplant rejection in both lamellar and penetrating transplantation settings. The rejection rate of high-risk transplants can be as high as 90%, irrespective of current treatment modalities. However, many patients who are blind from corneal diseases fall into this category after an inflammatory, infectious, traumatic or chemical insult. Our long-term goal is to elucidate the underlying mechanisms of LG using various in vivo corneal models and in vitro cell culture systems, a necessary prerequisite to the development of new therapeutic protocols. Our main hypothesis is that corneal LG is mediated by specific lymphatic factors and the interactions between lymphatic endothelial cells (LECs) and extracellular matrix (ECM), which can be modulated to interfere with LG and graft rejection. 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.
Our specific aims are: 1) investigate LG and valve formation in lamellar corneal transplantation using lymphatic fluorescent transgenic mice, live imaging technology, and neutralizing antibodies; 2) define the interaction between LECs and ECM using LEC culture system and mutant mice; and 3) assess the role of Wnt5a in high-risk corneal transplantation using conditional knockout mice and siRNAs. Research on corneal LG has broader clinical implications beyond the treatment of ocular diseases alone since lymphatic dysfunction is associated with a wide array of disorders, which include but are not limited to cancer metastasis, diabetes, inflammation, infection, obesity, hypertension and lymphedema.
Lymphatic vessel formation accompanies many corneal diseases after an inflammatory, infectious, traumatic, chemical, or immunogenic insult. It is 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 fundamental mechanisms underlying lymphatic formation and offer new therapeutic strategies to manage transplant rejection in different settings, and potentially other lymphatic and immune diseases in the body, such as cancer metastasis, diabetes, and lymphedema.
| 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 |
Showing the most recent 10 out of 25 publications
