Role of growth and differentiation factors in retinal ganglion cell development

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Role of Growth and Differentiation Factors in Retinal Ganglion Cell Development Glaucoma is among the leading causes of blindness, affecting roughly 60 million people worldwide.! Retinal ganglion cell and optic nerve degeneration are the major symptoms that result in permanent loss of vision in the patients. Currently, lowering intraocular pressure (IOP) is the only way to treat glaucoma; however, IOP reduction is not always sufficient to stop the underlying progression of RGC death. Understanding the intrinsic and extrinsic factors involved in RGC development and their application in cell- based therapies are critical therapeutic objectives for reversing vision loss from glaucoma and other optic neuropathies. Growth and differentiation factor 11 (GDF-11) was reported to negatively regulate RGC differentiation. Interestingly, we have found that another GDF member, GDF-15, was shown to positively regulate hippocampal neurogenesis. In retinal progenitor cell (RPC) culture, GDF-11 and GDF-15 regulate opposing RGC fate and mediate different Smad signaling. Based on our preliminary data, I hypothesize that GDF-15 promotes RGC differentiation and neurite patterning during development, and that Smad-2 signaling is important for RGC differentiation during retinal development. To address this hypothesis, I will determine the levels of RGC marker expression in PRC culture during embryonic stages in the presence of GDF-11 or GDF- 15 by qPRC and Western blot. To investigate the effects of GDFs in retinal development, I will use a floxed GDF-11 or Smad-2 allele to conditionally knock-out target genes in Chx10 expressing retinal cells at different developmental time points. In addition, I will apply GDF-15 in a novel directly induced RGC (iRGC) protocol, which will engage the differentiation of RGCs from embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs). The overall goal of this study is to better understand how GDFs influences RGC differentiation, the mechanism behind the regulation and its application to stem cell replacement, highlighting it as a potential therapeutic strategy.