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Drug Screening for Neuroprotectants in Novel Zebrafish Models of Retinitis Pigmentosa

新型斑马鱼视网膜色素变性模型中神经保护剂的药物筛选

基本信息

批准号：
10182665
负责人：
Liyun Zhang
金额：
$ 40.94万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-30 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10182665
关键词：
Affect Behavior Biological Assay Biological Models Blindness CRISPR/Cas technology Categories Cell Death Cell Death Process Cell Survival Cells Cessation of life Clinical Trials DNA Sequence Alteration Data Degenerative Disorder Disease Disease Pathway Disease model Dose Drug Delivery Systems Drug Modelings Drug Screening Drug Targeting Etiology Exhibits Fishes Fluorescence Gene Targeting Genes Genetic Genetic Models Goals High Pressure Liquid Chromatography Human Inherited Intervention Investigation Kinetics Knock-out Label Larva Lead Link Measures Mediating Methods Modeling Molecular Monitor Mus Mutant Strains Mice Mutation Neuroprotective Agents Pathogenesis Pathology Pathway interactions Patients Pharmaceutical Preparations Pharmacology Phenotype Photoreceptors Play Poly(ADP-ribose) Polymerases Process Proteins Publishing Reader Research Resources Retina Retinal Cone Retinal Degeneration Retinal Diseases Retinitis Pigmentosa Rod Role Route Series Severities Signal Transduction Structure of beta Cell of islet System Testing Therapeutic Therapeutic Index Therapeutic Intervention Time Transgenic Organisms Translations Vision Visual Whole Organism Work Zebrafish base drug candidate drug discovery human disease improved in vivo inherited retinal degeneration inhibitor/antagonist insight mouse model mutant novel novel therapeutics photoreceptor degeneration preservation response retinal rods rho screening small molecule therapeutic evaluation

项目摘要

PROJECT SUMMARY Retinitis pigmentosa (RP), an inherited retinal degeneration (IRD) disease, is characterized by primary rod photoreceptor death followed by cone cell death; this results in irreversible vision loss. The rate of cell death in RP is relatively slow, providing a protracted time window for therapeutic intervention. However, pharmacological intervention capable of promoting photoreceptor survival remains an unmet need. While many mouse RP models have been established, accelerating drug discovery by conducting large-scale drug screens in mice is impractical. Zebrafish, however, are an established system for modeling human disease and testing therapeutic compounds. In particular, our previous studies have shown zebrafish are especially valuable for large-scale phenotypic drug screens. Thus, we generated genetic zebrafish RP models by knocking out RP associated genes (e.g. rho, pde6a, and pde6b) with fluorescently labeled rod photoreceptors for easy phenotype monitoring. We identified five models which exhibit various rates and severity of rod cell loss, a key feature of RP. In addition, while the disease etiology is unclear, our preliminary data and recent studies suggest that poly-ADP ribose polymerase (PARP) signaling, a key regulator of the parthanatos cell death pathway, plays a significant role. Therefore, we propose to utilize new zebrafish RP models to investigate photoreceptor cell death mechanism(s), and perform an in vivo phenotypic drug re-purposing screen to identify small molecules that preserve degenerating photoreceptors. In Aim 1, we will measure cellular changes and rod photoreceptor degeneration in the new RP models. In addition, we will evaluate the effect of suppressing poly-PARP signaling, a hall mark of PARP1 activation, to determine if photoreceptor degeneration is ameliorated. This will be accomplished using PARP inhibitors and knocking out PARP1. We will assess how the extent of rod degeneration affects visual function by conducting visual behavior assays with the new RP models. In Aim 2, we will use a phenotypic drug screening platform we developed to identify compounds promoting rod photoreceptors survival in our RP models. We previously screened ~3,000 drugs in over 350,000 zebrafish larvae with inducible rod degeneration and successfully identified retinal neuroprotectants showing efficacy in both fish and mouse models. Here, we will screen ~200 hit drugs, mostly human-approved, from that project. In Aim 3, we will validate the identified neuroprotectants in three RP genetic mouse models. This cross-species drug discover approach will accelerate the translation of identified drug for clinical trial, an approach which can applied to a number of degenerative disease models. Therefore, completion of this project will provide insight into the molecular basis of RP pathogenesis and identify compounds for RP clinical trials.

项目总结