Bo Chen PharmD, PhD
Assistant Professor of Ophthalmology and Visual Science and of Neurobiology
Retinal degenerative diseases; Retinal neurobiology; Signal transduction pathways; Gene network regulation
The retina is a thin layer of light-sensing neural tissue that is located in the back of the eye. There are 6 neuronal and 1 glial cell types in the retina. Photoreceptors are the most abundant cell type in the mammalian retina. They respond directly to light and mediate the first step in vision. However, photoreceptors are also the most vulnerable cell type in human blinding diseases because many genetic mutations lead to progressive photoreceptor death. Currently there is no treatment available for more than 100,000 Americans who suffer from the disease. Previously we found that HDAC4 gene transfer significantly prolonged the survival of photoreceptors in a mouse model for this type of the disease. Our research interests are 1) to further dissect out the molecular pathways for the survival effect mediated by HDAC4, previously known to act as a transcription repressor in the nucleus. It is of fundamental importance to understand how HDAC4 promotes neuronal survival when it is in the cytoplasm. From a therapeutic perspective, a better understanding of the molecular mechanism for HDAC4’s pro-survival effect may lead to a better therapeutic intervention to save photoreceptors; 2) to perform functional assessment in animal models whether visual function can be restored by HDAC4 gene delivery; 3) to investigate whether HDAC4 as well as other pro-survival factors can be used to protect other retinal cell types from degeneration such as retinal ganglion cells. Retinal ganglion cells are the primary target of glaucoma, the leading cause of blindness worldwide.
Extensive Research Description
Summary of past research: Histone deacetylases (HDACs) act as transcription repressor in the nucleus to regulate tissue differentiation. The initial study of HDACs in the retina using an HDAC inhibitor demonstrated that HDACs play an important role in neuronal survival and photoreceptor development (BMC Dev Biol. 2007 Jun 29;7:78). When focused on individual HDACs using genetic manipulations in live animals, HDAC4, surprisingly localized mainly in the cytoplasm of retinal neurons, was found to be essential for neuronal survival during normal development. More interestingly, HDAC4 rescues photoreceptor degeneration in a diseased mouse retina that harbors a same genetic mutation that causes photoreceptor death and eventual blindness in human patients. The survival promoting effect of HDAC4 lies, at least in part, in the cytoplasm and works through stabilization of HIF1alpha, an unstable protein involved in the control of oxygen homeostasis. The findings about HDAC4 are entirely novel and point to a powerful therapeutic intervention in retinal degenerative diseases (Science, 2009 Jan 9;323(5911):256-9).