Retinal development occurs as a common retinal progenitor cell is differentiated into the seven classes of retinal neurons and supporting cells that organize into the three layers of the retina. This developmental process has primarily been studied in mace, as it takes place largely in utero, and the difficulty of obtaining human fetal tissue has put significant limitations on the ability to study the detailed mechanisms of early human retinal development. Understanding the genetic complexity of retinal cell fate decisions and cell lineages holds implications for our understanding of retinal disease. Retinal diseases can cause the dysfunction and death of specific retinal cell types, leading to vision loss and blindness in patients. Many genes associated with retinal diseases have also been implicated in normal retinal development, and knowledge of the correct molecular processes will give context to abnormal processes observed in disease states. Recently, human stem cell- derived retinal organoids have become an established model for studying the cellular and molecular processes of retinal development. The goal of this study is to perform simultaneous RNA sequencing and lineage tracing in vivo in murine retinas and in vitro in developing human retinal organoids at single-cell resolution in order to create detailed maps of human and mouse retina formation. The proposed study will build upon our understanding of mice as a model organism for retinal studies and allow the identification of genes and pathways involved in the precise cell fate decisions that occur during human retinal development. The ultimate comparison of these two model systems may further highlight and prioritize genes of key importance. This knowledge will help to develop and improve therapeutic strategies for treating retinal diseases. This proposal explains a research strategy and training plan to develop the principal investigator, Ms. Claire Wenger, throughout her graduate education. Ms. Wenger has completed her third-year as a graduate student in the Human Genetics Predoctoral Training Program at Johns Hopkins School of Medicine. After graduating, it is her goal to continue to pursue vision research and embark on a career as a principal investigator at a research- based institution. Ms. Wenger?s education must be thorough and interdisciplinary in order to develop her skills in molecular and cellular biology, bioinformatics, responsible conduct of research, scientific communication, and mentorship. Her training plan includes coursework, seminars, meetings, and laboratory skills taught to her by a diverse set of mentors. The proposed research and training strategies will provide Ms. Wenger with the necessary tools to excel in her graduate career and successfully attain her future goals.
Improving our understanding of normal human retinal development will help give us insight into the abnormal processes that cause impairment and loss of vision in retinal diseases. The goal of this study is to identify gene expression changes that are associated with specific cell fates in the developing human and murine retinas. The results of this study may highlight species-specific differences and lead to new molecular targets for drug treatments and cell-based therapeutic strategies against retinal diseases.