Exploring Mechanisms in Retinal Development/Homeostasis, Retinal Immune Surveillance and Diabetic Retinopathy Using Forward Genetics
利用正向遗传学探索视网膜发育/稳态、视网膜免疫监视和糖尿病视网膜病变的机制
基本信息
- 批准号:10316653
- 负责人:
- 金额:$ 45.1万
- 依托单位:
- 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 2026-07-31
- 项目状态:未结题
- 来源:
- 关键词:AnatomyBlindnessCRISPR/Cas technologyCellsCo-ImmunoprecipitationsCollaborationsComplexConceptionsDefectDevelopmentDiabetes MellitusDiabetic RetinopathyDiseaseEligibility DeterminationEnsureEthylnitrosoureaFunctional disorderFundingFundusGene ProteinsGenerationsGenesGeneticGenomeGenotypeGoalsHealthHomeostasisImmuneImmunologic SurveillanceInflammatoryInjectionsInjuryInvestigationKnowledgeLeadLightLiteratureMaintenanceMass Spectrum AnalysisMeasurementMediatingMeiosisMicrogliaModelingMolecularMusMutagenesisMutateMutationNatural regenerationNatureNeurogliaNeuronsNitrosourea CompoundsOptical Coherence TomographyPathway interactionsPhenotypePhotoreceptorsPhysiologyPlayPredispositionProcessProteomicsProtocols documentationPublishingRecoveryReportingResearchRetinaRetinal DefectRetinal DiseasesRoleScienceSpottingsStreptozocinSuggestionSystemTechniquesTechnologyTestingThickThinnessVisionbasecausal variantcell typeexperimental studyexposure pathwayforward geneticsgene discoverygenetic approachgenetic pedigreeimmunoregulationimprovedinsightinterestmouse genomemutantnew therapeutic targetnovelnovel therapeuticsouter plexiform layerretinal imagingretinal regenerationribbon synapsescreeningsingle-cell RNA sequencingsuccesstraffickingtreatment strategy
项目摘要
Project Summary
Defects in the carefully orchestrated processes of retinal development, homeostasis and retinal immune
surveillance lead or contribute to a wide range of diseases. It is now clear that genetics not only play a role in
these processes but may also modulate diabetic retinopathy. Our short-term goal is to identify and characterize
gene/protein defects and molecular pathways that lead to abnormal retinal development/homeostasis, altered
retinal immune surveillance and modulation of diabetic retinopathy. The long-term goal is to leverage our
research discoveries to understand retinal disease processes, and to identify novel therapeutic opportunities.
We propose that a high-throughput and unbiased strategy provides an ideal approach to discovery of
gene/phenotype associations in this setting. In collaboration with Nobel laureate Bruce Beutler, we will employ
a robust state-of-the-science and unbiased forward genetics approach, in which thousands of new random
mutations are generated and mice demonstrating retinal anomalies are identified by screening using fundus
photographs and OCT.
Our approach has significant advantages compared to other existing protocols. Most importantly, ours is
the first and only protocol in which all mice have been pre-genotyped at all mutant loci. In addition, the large
scale of our system and the large pedigree size will also add to the discovery power. Together, these advantages
will allow us to identify and pursue novel gene/phenotype associations related to retinal development,
homeostasis and disease. We have identified over 43 gene-phenotype associations after covering just 8% of the
mouse genome. Of these, 12 genes have weak associations to the retina in the literature, and another 20 genes
have not been reported in association to the retina. This is strong evidence that expanding our screening to
include the remaining 92% of the mouse genome will yield many more gene-phenotype associations related to
retina development, homeostasis and immune surveillance. Of note, our proposal starts by selecting a few of
the most promising genes we have already identified for further study. We will harness the power of
CRISPR/Cas9 gene editing, single cell RNA sequencing, co-immunoprecipitation experiments with highly
sensitive mass spectrometry and proteomics analysis, our recently published light injury model and other
techniques to explore the mechanisms of these associations. We will also apply the streptozotocin model of
diabetic retinopathy to our OCT retinal imaging pipeline to identify genes that can modulate early diabetic
retinopathy. This proposed research will advance our knowledge of retinal health and disease, and we anticipate
that it will lead to the identification of new therapeutic avenues.
项目总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Rafael Ufret-Vincenty其他文献
Rafael Ufret-Vincenty的其他文献
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{{ truncateString('Rafael Ufret-Vincenty', 18)}}的其他基金
Exploring Mechanisms in Retinal Development/Homeostasis - Admin. Supplement
探索视网膜发育/稳态的机制 - 管理。
- 批准号:
10636145 - 财政年份:2021
- 资助金额:
$ 45.1万 - 项目类别:
Exploring Mechanisms in Retinal Development/Homeostasis, Retinal Immune Surveillance and Diabetic Retinopathy Using Forward Genetics
利用正向遗传学探索视网膜发育/稳态、视网膜免疫监视和糖尿病视网膜病变的机制
- 批准号:
10672979 - 财政年份:2021
- 资助金额:
$ 45.1万 - 项目类别:
Role of complement factor H and immunity in AMD: a novel transgenic model
补体因子 H 和免疫在 AMD 中的作用:一种新型转基因模型
- 批准号:
8345535 - 财政年份:2012
- 资助金额:
$ 45.1万 - 项目类别:
Role of complement factor H and immunity in AMD: a novel transgenic model
补体因子 H 和免疫在 AMD 中的作用:一种新型转基因模型
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8546385 - 财政年份:2012
- 资助金额:
$ 45.1万 - 项目类别:
Role of complement factor H and immunity in AMD: a novel transgenic model
补体因子 H 和免疫在 AMD 中的作用:一种新型转基因模型
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8708875 - 财政年份:2012
- 资助金额:
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