Many retinal degenerative diseases that lead to vision impairment and blindness involve the loss of photoreceptors in the retina. Current therapies delay the progression of disease, but they do not prevent or reverse the loss of photoreceptors. In animal studies, cellular therapy using embryonic stem cell (ESC)-derived retinal neurons have shown promising results; the cells integrate into the host retina and restore some light response. For my career, I envision focusing on bringing human ESCs closer to clinical application, using them as an unlimited source of cells for transplants to restore vision in patients with retinal degeneration. To achieve this, I will continue my postdoctoral training under Dr. Thomas Reh at the University of Washington. Dr. Reh and his laboratory provide the best environment for this proposal; Dr. Reh is a pioneer in retinal development, retinal regeneration and differentiation of ESCs into retinal neurons. In addition, he has mentored many postdoctoral fellows towards successful academic careers. Under his guidance, I will study the role of miRNAs and their targets in ESCs during retinal differentiation. It currently takes several weeks to months to produce retinal neurons from mESCs and hESCs, respectively. Speeding up differentiation will make hESCs a more viable therapeutic option. In the mouse retina, miRNAs have been shown to regulate development; overexpression of Let-7a, miR-125b, and miR-9 (Late Progenitor-miRNAs) accelerate developmental timing. Furthermore, this effect is mediated by their direct targets, Lin28b and Protogenin, and overexpression of either of these two proteins slowed down development. We hypothesize that miRNAs and their targets regulate timing in differentiating mouse and human ESCs similarly as in the mouse.
In Aim 1, I will test whether overexpression of LP-miRNAs will accelerate development of mESC-derived retina.
In Aim 2, I will determine whether Lin28b and Prtg regulate timing in in vivo and in mESC cultures. I will also perform structure-function studies to examine how Prtg may mediate this effect. These proposed studies will expand our understanding of the factors that control developmental timing, and help derive retinal neurons from ESCs more efficiently for use in cell therapy.

Public Health Relevance

Loss of retinal neurons is the leading cause of vision impairment and blindness, and cellular therapy to replace these lost cells is an attractive approach to restore vision. Embryonic stem cells can be differentiated into retinal neurons and offer a promising unlimited source of new cells for transplantation. In this proposal, we attempt to improve the generation of retinal neurons from mouse and human embryonic stem cell lines.

National Institute of Health (NIH)
National Eye Institute (NEI)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1)
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Agarwal, Neeraj
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University of Washington
Anatomy/Cell Biology
Schools of Medicine
United States
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Hoshino, Akina; Ratnapriya, Rinki; Brooks, Matthew J et al. (2017) Molecular Anatomy of the Developing Human Retina. Dev Cell 43:763-779.e4
Chao, Jennifer R; Lamba, Deepak A; Klesert, Todd R et al. (2017) Transplantation of Human Embryonic Stem Cell-Derived Retinal Cells into the Subretinal Space of a Non-Human Primate. Transl Vis Sci Technol 6:4