Research Abstract:
My laboratory uses conditional gene knockouts, transgenic mice and microarray analysis to define the signaling pathways that are required for the normal development of the eye. We also study rodents and human subjects to identify the causes of, and design preventions for, age-related cataracts, the most common cause of blindness in the world. Our recent studies have also identified new risk factors for glaucoma. Current projects: 1) We are using tissue-specific deletion of receptors and signal transducers in the transforming growth factor-beta (TGFbeta) superfamily (BMP/TGFbeta/activin) to define the functions of these pathways in eye development. Embryos lacking these receptors and other key transcription factors are being compared to wild type embryos using laser microdissection and microarray analysis. 2) Using similar approaches, we are deleting fibroblast growth factor (FGF) receptors during eye development to test their functions alone and together with members of the TGFbeta superfamily. 4) Intraocular oxygen levels regulate the postnatal growth of the lens and HIF-1, the major hypoxia-regulated transcription factor, mediates the effect of oxygen on lens growth. Because lens size is a major risk factor for human cataracts, we are using HIF transgenic mice and microarray analysis to identify the molecular pathway(s) by which HIF regulates lens growth in vivo. 5) We identified a metabolic pathway in the eye that appears to protect the lens from exposure to excess oxygen. We are determining how this pathway functions and how it is inactivated in cataract patients. 6) Together with collaborators at Wash U, UC Santa Barbara and in industry, we are developing means to protect the lens for exposure to excessive oxygen. We will apply these interventions to patients who have had retina surgery, a therapeutic intervention that leads to cataract formation within two years in over 90% of cases. If successful, these studies will lead to treatments to prevent age-related cataracts in the general population.
Selected Publications:
Huang J, Dattilo LK, Rajagopal R, Liu Y, Kaartinen V, Mishina Y, Deng C-X, Umans L, Zwijsen A, Roberts AB, Beebe DC. FGF-regulated BMP signaling is required for eyelid closure and to specify conjunctival epithelial cell fate. Development 2009 May 136(10):1741-50.
Shui Y, Holekamp NM, Kramer BC, Crowley JR, Wilkins MA, Chu F, Malone PE, Mangers SJ, Hou JH, Siegfried CJ, Beebe DC. The Gel State of the Vitreous and Ascorbate-dependent Oxygen Consumption: Relationship to the Etiology of Nuclear Cataracts. Arch Ophthalmol 2009 127(4):1-8.
Rajagopal R, Huang J, Dattilo LK, Kaartinen V, Deng C-X, Umans L, Zwijsen A, Roberts AB, Bottinger EP, and Beebe DC. The Functions of the type I BMP receptor, Acvr1 (Alk2), in Lens Development: Cell Proliferation, Terminal Differentiation and Survival. Invest Ophthalmol Vis Sci. 2008 Nov 49(11):4953-60.
Shui Y, Arbeit JM, Johnson RS and Beebe DC. HIF-1: an Age-dependent Regulator of Lens Cell Proliferation. Invest Ophthalmol Vis Sci. 2008 49(11):4961-70.
Shui Y, Beebe DC. Age-dependent control of lens growth by hypoxia. Invest Ophthalmol Vis Sci. 2008 Mar 49(3):1023-9.
Last Updated: 08/11/2009 |