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Genetic and Chemical Screens for Factors Regulating Retinal Regeneration

遗传和化学筛选调节视网膜再生的因素

基本信息

批准号：
8547957
负责人：
JEFFREY MUMM
金额：
$ 17.79万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8547957
关键词：
Ablation Biological Models Blindness Cell Culture Techniques Cell Cycle Kinetics Cells Chemicals Cicatrix Communities Development Disease Exogenous Factors Eye Fishes Genes Genetic Genetic Screening Hair Cells Human Human Development Individual Injury Kinetics Lead Libraries Mammals Measures Modeling Molecular Molecular Mechanisms of Action Natural regeneration Neuroglia Neurons Nitroreductases Outcome Photoreceptors Process Property Reporter Research Resources Retina Retinal Retinal Photoreceptors Series Shapes Source Specificity Stem cells System Testing Therapeutic Tissues Toxic effect Transgenic Organisms Vision Vision Disorders Zebrafish cell type chemical genetics dosage drug discovery high throughput screening in vivo mutant novel programs public health relevance regenerative regenerative therapy repaired response retinal neuron retinal progenitor cell retinal regeneration retinal rods rho screening small molecule stem stem cell biology therapeutic development tissue regeneration

项目摘要

PROJECT SUMMARY The mammalian retina does not repair itself following retinal cell loss. This fact led to the assumption that the mammalian retina is incapable of self-repair. However, recent studies suggest the potential for the retina to regenerate is intact, even in humans; human M¿ller glia cell cultures are capable of giving rise to retinal neurons, and M¿ller glia cells can function as injury-induced retinal stem cells in mammalian models when stimulated with exogenous factors, albeit functional repair remains elusive. Together, these studies suggest that: 1) the regenerative potential of M¿ller glia cells is conserved in humans and; 2) an understanding of how retinal stem cells are regulatedin particular, M¿ller glia responses to cell losscould aid development of regenerative therapies for diseases causing vision loss and blindness. M¿ller glia recently emerged as the stem cells responsible for robust retinal regeneration in zebrafish, providing an excellent model system for investigating how the regenerative potential of M¿ller glia cells is regulated. To date, zebrafish studies have implicated only a few molecular regulators of retinal regeneration. To expand mechanistic understanding of retinal repair, we propose to use unbiased genetic and chemical screening approaches to: 1) identify regeneration deficient zebrafish mutants that develop a normal retina but fail to regenerate rod photoreceptors following cell-specific ablation (Aim 1), and 2) discover compounds that promote retinal regenerationincrease the pace of rod cell replacement kinetics or promote rod cell regeneration in mutants (Aim 2). We have established a transgenic line in which selective ablation of rod photoreceptor cells can be induced. Using this line for an ongoing pilot screen, we have succeeded in identifying three regeneration deficient mutants and numerous potential mutants that display incomplete rod cell replacement, demonstrating proof of principle of the genetic screening strategy. Chemical screens will use an in vivo high-throughput screening (HTS) system we developed for measuring changes in fluorescent reporter levels in individual fish. This system allows us to discover compounds that effect rod cell regeneration by quantifying the kinetics of cell loss and replacement in thousands of fish per day. Defining cellular and molecular mechanisms that underlie how mutants disrupt and compounds modulate the regenerative process will serve to further our understanding of retinal stem cell biology. Additionally, this project will generate/validate new and useful resources for the research community: 1) novel mutant zebrafish lines for defining how regeneration is controlledranging from cell-specific repair to mechanisms regulating whole tissue regeneration, and; 2) an in vivo HTS platform for drug discovery that is applicable to a broad range of research programs.

项目总结