Injuries or diseases that kill retinal neurons and receptors block vision at it source. The resulting blindness is permanent. The inability to repair in the retina is a hallmark of the human central 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 mechanisms that regulate the birth, death and regeneration of neurons and photoreceptors in the vertebrate retina. This program of research utilizes the zebrafish, because the fish retina is the only vertebrate CNS tissue where intrinsic stem cells can regenerate a single neuronal type that integrates into an existing circuit or can regenerate all cell types that completely restore the original tissue. Thus, investigating stem cell-based neuronal and photoreceptor regeneration in the teleost retina will advance our knowledge of mechanisms that govern the ability of intrinsic stem and progenitor cells to restore neural circuits in the injured brain. The resulting knowledge will guide the therpeutic use of transplanted 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 photoreceptors.
Specific Aim 1 will investigate the function of the bHLH transcription factor, NeuroD, in both the developing and regenerating retina.
Specific Aim 2 will test the hypothesis that microglia play a neurogenic role during photoreceptor regeneration.
Specific aim 3 will test the hypothesis that the soluble growth factor, midkine-a, controls aspects of retinal development in larval zebrafish and photoreceptor regeneration in adults. Together these specific aims represent a focused and integrated research program to test specific hypotheses of the biology and regulation of retinal development and neuronal regeneration in the vertebrate nervous system.

Public Health Relevance

Photoreceptors initiate the first step in vision, and in the human retina the death of photoreceptors leads to permanent blindness. The Specific Aims descibed in this proposal will investigate the mechanisms by which intrinsic stem and progenitor cells regenerate photoreceptors in an adult retina. This work is highly relevant to human health, because it explores the molecular mechanisms employed by adult stem cells to repair the retina and brain and will provide information relevant to the therapeutic use of neural stem and progenitor cells in humans.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY007060-23
Application #
8318776
Study Section
Special Emphasis Panel (ZRG1-CB-G (90))
Program Officer
Greenwell, Thomas
Project Start
1987-05-01
Project End
2015-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
23
Fiscal Year
2012
Total Cost
$519,849
Indirect Cost
$185,541
Name
University of Michigan Ann Arbor
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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
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
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
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
Calinescu, Anda-Alexandra; Raymond, Pamela A; Hitchcock, Peter F (2009) Midkine expression is regulated by the circadian clock in the retina of the zebrafish. Vis Neurosci 26:495-501
Ochocinska, M J; Hitchcock, P F (2009) NeuroD regulates proliferation of photoreceptor progenitors in the retina of the zebrafish. Mech Dev 126:128-41
Calinescu, Anda-Alexandra; Vihtelic, Thomas S; Hyde, David R et al. (2009) Cellular expression of midkine-a and midkine-b during retinal development and photoreceptor regeneration in zebrafish. J Comp Neurol 514:1-10
Ochocinska, Malgorzata J; Hitchcock, Peter F (2007) Dynamic expression of the basic helix-loop-helix transcription factor neuroD in the rod and cone photoreceptor lineages in the retina of the embryonic and larval zebrafish. J Comp Neurol 501:1-12
Chang, Bo; Dacey, Mark S; Hawes, Norm L et al. (2006) Cone photoreceptor function loss-3, a novel mouse model of achromatopsia due to a mutation in Gnat2. Invest Ophthalmol Vis Sci 47:5017-21

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