Genomic investigations, gene mapping and molecular genetics of glaucoma, age-related macular degeneration, and high myopia
Genome wide association studies with SNP and microsatellite marker scanning, family linkage analysis, fine mapping, sequencing, cloning, and gene function analysis to identify disease loci and characterize disease genes. More than 50 families, 2,000 patients and 500 control subjects are involved in these studies.
Primary Open Angle Glaucoma (POAG)
We were the first group to propose and confirm gain-of-function pathology in glaucoma caused by myocilin mutation. We have also identified 2 novel POAG chromosomal loci, GLCA1M and GLCA1N. We have recently identified a new susceptible gene for glaucoma and are currently characterizing its structure and properties. We participate in mapping CAV1 and CAV2 for POAG.
Primary Angle Closure Glaucoma (PACG)
We participate in mapping the first loci for PACG.
Age-related macular degeneration (AMD)
We identified a major AMD gene, HTRA1, in collaboration with a Yale University research group. We are currently investigating the mechanism of AMD through characterization of the biological functions of HTRA1 and other currently known AMD genes.
High myopia (HM)
We published the first candidate gene for high myopia, TGIF, which contributes modifying effects. We have identified a new HM locus, MYP16. We also discovered dinucleotide repeats in the PAX6 P1 promoter are associated with high myopia. Currently we are continuing our mapping for the myopia gene.
Molecular mechanisms of Bietti crystalline dystrophy, retinitis pigmentosa Graves’ ophthalmopathy, corneal dystrophies, congenital cataracts
We investigate the pathologic mechanisms of specific eye diseases with serious consequences of visual impairment and even blindness. Our results have been contributing to understanding of the pathogenesis for prevention and treatment.
Bietti crystalline dystrophy (BCD)
Our genotyping, clinical phenotyping, and biochemical studies have discovered the association with dysfunctions of lipid metabolism.
Graves’ ophthalmopathy (GO)
We have shown the contribution of CTLA-4 to Graves Disease but not GO. Currently we are collecting data on the autoantibodies specific to GO and novel gene expressions for early diagnosis, and delineating genetic and environmental factors that lead to GO.
Retinitis pigmentosa (RP)
Our work has affirmed the contributions of the SNRNP200, NR2E3, RHO and RP1 genes on the mechanism of RP.
Corneal dystrophies
In collaboration with Singapore Eye Research Institute, a novel gene in an endothelial form of cornea dystrophy has been identified.
Uveitis
We study the molecular mechanisms of anterior uveitis. Specific genotyping and interactive analysis have shown complex involvement of susceptible genes. We have shown HLA-B27 status affecting interactive effects of MnSOD and CCL2 in anterior uveitis. Our further investigations give evidence of strong differential risks due to variants in CFH and CFB in the complement alternative pathway, while other complement pathway genes, SERPING1 (C1INH), C3 and C5, as well as IL2_21 region and IL27 involving in T-cell response, confer limited risk. There are ongoing genome wide study and target sequencing programmes that will lead to identification of major genes in specific uveitis forms.
Congenital cataracts
We use an exclusion strategy to identify the disease causing mutations of specific congenital families. Characterizing the gene functions and properties throws light on the mechanism of cataract development.
Molecular characterization and epi-genetics of retinoblastoma (Rb)
We are the first group to delineate effects of loss of heterozygosity, microsattelite instability, promoter hypermethylation of tumor suppressor genes, RB1, MLH1, RASSlFA, and DNA repair gene (MGMT) on the tumorigenesis of retinoblastoma. Currently we are characterizing Rb genomics and chromosomal copy number variation.
Molecular biology and toxicity studies of ocular cells: trabecular meshwork cells, retinal ganglion cells, retinal pigment epithelial cells, human endothelial vascular cells. Biological effects of herbal medicine
We have been conducting series of cellular and molecular studies to examine toxicity and biological effects of new drug regimens and herbal medicine.
Molecular biology of ocular stem cells
We published the first paper on miRNA characterization in human corneal progenitor cells. We study the biology of cornea progenitor cells, conventionally termed limbal stem cells, with a view to identify specific surface markers and understand the regulatory mechanisms of their differentiations.
Herbal molecules for treatment of eye diseases
Herbal medicine has been in use for treatment of human ailments for millenniums across civilizations. Traditional herbal medicine is still in use today in therapies in all developed regions. Almost all such therapies involve mixed formulae with unspecified extraction procedures of a wide spectrum of plants. For eye diseases, our search of the literature in English has resulted in 7 categories of plants or herbal products described for ocular effects: carotenoids, Ginkgo biloba extract, androcyanins, resevratrol, catechins,omega-3-fatty acids, and isoliquiritigenins.We had shown that Ginkgo biloba extract (GBE) effectively suppressed steroid-induced ocular hypertension in rabbits, possibly mediated by preventing steroid-associated myocilin expression in trabecular meshwork cells, which became less prone to apoptosis. GBE, therefore, can preserve the functional outflow pathway and can be an alternative therapeutic agent for steroid-induced ocular hypertension. Among isoliquiritigenin (ISL) from licorice, epigallocatechin gallate (EGCG) from green tea, resveratrol (Rst) from grapes, and gambogic acid from resin of Garcinia hurburyi, we found ISL, EGCG, and Rst highly effective in suppressing endothelial cell proliferation and migration, with low cytotoxicity. They are potentially useful for anti-angiogenic therapies by virtue of their low effective dosages and small molecular sizes for easy penetration through tissue cells. We have adopted in vivo models to study these molecules in regulated angiogenesis using chick chorioallantoic membrane vascularization and pathological angiogenesis using chemical-induced corneal neovascularization, laser photocoagulation-induced choroidal neovascularization and oxygen-induced retinal neovascularization in mice. Our experimental rat models include sodium iodate induced retinal degeneration and LPS induced ocular inflammation.
Advancements in analytical technologies
We do research especially on separation technologies to aid in our research on pharmacokinetics, drugs effects and nucleic acids studies. We are also utilizing proteomic technologies to analyze human tear in inflammatory eye diseases.
