Injuries or diseases that kill retinal neurons or photoreceptors block vision at it source. The inability to repair the retina is a hallmark of the human nervous system; neurons that die are not replaced and functions that are lost are not recovered. This bleak outcome is a driving force for research on neural stem cells and the field of regeneration biology. The long-term objective of this project is to elucidate the molecular mechanisms that regulate the birth, death and regeneration of neurons and photoreceptors in the vertebrate retina. This program of research utilizes the zebrafish retina, the only vertebrate CNS tissue in which intrinsic stem cells can regenerate a single neuronal type that integrates into existing synaptic circuits or regenerate all cell types that completely restore the original tissue. Investigating stem cell-based developmental and regenerative neurogenesis will advance our knowledge of the mechanisms that govern retinal stem and progenitor cells and will guide the therpeutic use of stem and progenitor cells to treat retinal injuries, blindness and disease.
Three Specific Aims are proposed, each directed toward revealing mechanisms that regulate the genesis and regeneration of retinal neurons and photoreceptors.
Specific Aim 1 will test the hypothesis that photoreceptor genesis is governed through post-transcriptional regulation of NeuroD by the the microRNA, miR-18a.
Specific Aim 2 will determine the combined and independent functions of the Midkine paralogs during retinal development and photoreceptor regeneration.
Specific aim 3 will test the hypothesis that the matrix metalloproteinase, MMP9, is induced in Mller glia by TNF-?, and together these molecules are components of an acute inflammatory response that governs photoreceptor regeneration. Together these specific aims represent a focused and integrated research program to test specific hypotheses about the biology and regulation of developmental neurogenesis and adult photoreceptor regeneration in the vertebrate retina. This program of research will expand our knowledge of photoreceptor death and regeneration and the molecular mechanisms that regulate retinal stem and progenitor cells. These studies also will have implications for the NEI Audacious Goals Initiatives.
The work described in this proposal seeks to identify molecular mechanisms that govern how both neurons and non-neuronal cells respond to a brain injury and how one might utilize stem cells to affect brain repair. This work is performed using the retina as a model brain tissue. Our studies will examine embryonic retinal development, to identify basic developmental mechanisms, and the adult retina, to study photoreceptor regeneration. This project is relevant to the NEI's mission, because it pertains to developing fundamental knowledge regarding the regeneration of retinal neurons and circuits.
|Walsh, Caroline E; Hitchcock, Peter F (2017) Progranulin regulates neurogenesis in the developing vertebrate retina. Dev Neurobiol 77:1114-1129|
|Gramage, Esther; D'Cruz, Travis; Taylor, Scott et al. (2015) Midkine-a protein localization in the developing and adult retina of the zebrafish and its function during photoreceptor regeneration. PLoS One 10:e0121789|
|Taylor, Scott M; Alvarez-Delfin, Karen; Saade, Carole J et al. (2015) The bHLH Transcription Factor NeuroD Governs Photoreceptor Genesis and Regeneration Through Delta-Notch Signaling. Invest Ophthalmol Vis Sci 56:7496-515|
|Gramage, E; Li, J; Hitchcock, P (2014) The expression and function of midkine in the vertebrate retina. Br J Pharmacol 171:913-23|
|Huang, Tao; Cui, Jianlin; Li, Lei et al. (2012) The role of microglia in the neurogenesis of zebrafish retina. Biochem Biophys Res Commun 421:214-20|
|Taylor, Scott; Chen, Jing; Luo, Jing et al. (2012) Light-induced photoreceptor degeneration in the retina of the zebrafish. Methods Mol Biol 884:247-54|
|Luo, Jing; Uribe, Rosa A; Hayton, Sarah et al. (2012) Midkine-A functions upstream of Id2a to regulate cell cycle kinetics in the developing vertebrate retina. Neural Dev 7:33|
|Thomas, Jennifer L; Ochocinska, Margaret J; Hitchcock, Peter F et al. (2012) Using the Tg(nrd:egfp)/albino zebrafish line to characterize in vivo expression of neurod. PLoS One 7:e29128|
|Ghosh, Amiya K; Murga-Zamalloa, Carlos A; Chan, Lansze et al. (2010) Human retinopathy-associated ciliary protein retinitis pigmentosa GTPase regulator mediates cilia-dependent vertebrate development. Hum Mol Genet 19:90-8|
|Craig, Sonya E L; Thummel, Ryan; Ahmed, Hafiz et al. (2010) The zebrafish galectin Drgal1-l2 is expressed by proliferating Muller glia and photoreceptor progenitors and regulates the regeneration of rod photoreceptors. Invest Ophthalmol Vis Sci 51:3244-52|
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