My ultimate goal is to elucidate the epigenetic mechanisms that control retinal development in order to identify novel targets to regenerate tissues lost in the retinal degenerative diseases. These blinding disorders have few treatments and afflict the majority of individuals I care for as a retinal physician and surgeon. For example, age-related macular degeneration (AMD), in which photoreceptors degenerate leading to vision loss, is a disease that affects 10 million Americans. One regenerative strategy for AMD is pluripotent stem cell (PSC)-derived photoreceptor transplantation. However, derivation of PSC-derived retinal progenitor cells (RPCs)?tissue-specific precursors to photoreceptors?remains inefficient, donor-dependent, and poorly understood. To better understand how RPCs arise, and to achieve the initial steps of my career goals, I have planned a three-year, mentored career development program designed to foster my transition to an independent investigator. I have devised didactic and hands-on training aims that integrate stem cells and chromatin dynamics with state-of-the-art epigenetic techniques. This work will take place at University of Michigan (U-M), an outstanding environment with a track record of nurturing young faculty toward independent research careers. My primary mentor, Yali Dou, is an internationally recognized expert in the field of epigenetic regulation of transcription. Sally Temple, co-mentor, is a pioneer in neural stem cells and in defining their developmental transcriptome. Thomas Gardner, U-M K12 Principal Investigator and senior clinician-scientist, whose work focuses on diabetic retinopathy, will serve as a career mentor. This diverse and accomplished team will foster my training aims, career goals, and my efforts to address the central research theme: how an epigenetic enzyme, Mll1, orchestrates formation of RPCs from PSCs. The rationale for this proposal is that by determining the role of Mll1 in retinal differentiation, knowledge will be gained about unknown epigenetic mechanisms that govern retinal formation. We have recently discovered the Mll1-Rx retinal developmental axis, and have also found that Mll1 regulates retinal Meis1. Dysregulation of Mll1, Meis1, or Rx disrupts mammalian retinal development, but how this occurs remains unknown. To address this knowledge gap, the proposed research aims to: 1) determine whether Mll1 deficiency impairs generation of RPCs via Meis1 and Rx repression; and 2) define Mll1-dependent transcriptome and enhancer networks within the retinal Mll1-Rx axis. To accomplish these aims, I will learn and apply innovative technologies such as gene editing, RNA interference, ChIP- and RNA-sequencing, and enhancer motif analysis. This integrated pipeline will allow genome-wide interrogation of targetable and clinically relevant epigenetic pathways in retinal development, and could ultimately be applied to retinal disease. Together, the insights, skills, and guidance gained from the proposed studies, career development plan, and mentorship team will facilitate my transition from a mentored clinician investigator to an independent, R01-supported, translational scientist.

Public Health Relevance

Retinal degenerative diseases, such as dry age-related macular degeneration, are common, incurable causes of blindness worldwide that lead to loss of independence, reduced quality of life and work productivity. This project uses a stem cell-based platform to study the role of Mll1, an important epigenetic protein that ?switches on? genes necessary for retinal development. This application has the potential to improve public health by adding to our understanding of retinal development and by using this newly gained knowledge to enhance stem cell-based therapies in order to restore vision.

National Institute of Health (NIH)
National Eye Institute (NEI)
Clinical Investigator Award (CIA) (K08)
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Special Emphasis Panel (ZEY1)
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Agarwal, Neeraj
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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Abalem, Maria Fernanda; Rao, P Kumar; Rao, Rajesh C (2018) Nystagmus and Platinum Hair. JAMA 319:399-400
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