MOLECULAR MECHANISMS OF HUMAN RETINAL DISEASE
Chen Rui
Baylor College Of Medicinecity: Houston country: United States (us)
Grant 5R01EY020540-02 from National Eye Institute
Keywords: Accounting; Affect; Alleles; Animal Model; base; Birth; Blindness; Clinical; clinical phenotype; Collection; Complement; Data; Defect; Diagnosis; Disease; disease-causing mutation; early onset; Electrophysiology (science); Electroretinography; European; Eye; Fundus; Gene Targeting; gene therapy; Genes; Genotype; Goals; Heterogeneity; Histology; Homozygote; Human; Immunohistochemistry; improved; infancy; Infant; Inherited; Knockout Mice; Lead; Leber`s amaurosis; Life; Light; Modeling; Molecular; Molecular Diagnosis; mouse model; Mus; mutant; Mutant Strains Mice; Mutation; Names; novel; Pathologic Nystagmus; Patients; Phenotype; Photoreceptors; Population; Preclinical Drug Evaluation; Prevalence; prevent; Prevention; Proteins; public health relevance; response; Retina; Retinal Defect; Retinal Diseases; Retinal Dystrophy; Retinitis Pigmentosa; Role; Screening procedure; Signs and Symptoms; subretinal injection; System; Testing; Transmission Electron Microscopy; Virus; Visual; Weaning
Relevance: The main goal of this project is to create a model of the human retinal disease called Leber congenital amaurosis (LCA), which is the leading cause of blindness in infants. In order to create more effective means of diagnosis, prevention, and treatment, we need a more detailed understanding of this devastating disease. Our model for LCA using mouse gene targeting will provide an essential platform for determining the exact defects in the eye and to conduct gene therapy studies to correct such defects
Project start date: 2011-02-01
Project end date: 2015-01-31
Budget start date: 1-FEB-2012
Budget end date: 31-JAN-2013
5R01EY020540-02 (2012): $409210
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to Chen Rui
MOLECULAR MECHANISMS OF HUMAN RETINAL DISEASE
Chen Rui, Dr.
Baylor College Of Medicinecity: Houston country: United States (us)
Grant 1R01EY020540-01A1 from National Eye Institute
Abstract: The long-term goal of this project is to improve both the diagnoses and the treatments of Leber congenital amaurosis (LCA). LCA is a set of inherited, early onset retinopathies that affect about 1 in 50,000 in the general U.S. population and accounts for more than 5% of all retinal dystrophies. The clinical phenotypes of LCA classically follow autosomal recessive modes of inheritance, are often severe, and are characterized by several visual perturbations identifiable at birth or within the first year of life, including infantile nystagmus, a variety of fundus changes, and minimal or absent responses on the electroretinogram. Consistent with this clinical heterogeneity, the molecular basis for LCA is also heterogeneous, with mutations in fifteen different genes associated with LCA. We recently identified the causative gene associated with LCA3, named SPATA7, which encodes a highly conserved but novel protein of unknown function and for which no animal models have been established. We have created null alleles of the mouse Spata7 gene and have shown that Spata7 homozygotes are viable but present severe retinal defects, recapitulating the major features of the human LCA3 condition. Significantly, SPATA7 mutations are associated with both LCA and early-onset retinitis pigmentosa (RP), suggesting that a detailed understanding of SPATA7 function could have broad implications for our ability to diagnose, prevent, and treat human retinal diseases. In this proposal, our Specific Aims are to Specific Aim 1. Study a mouse model for LCA3 Spata7 null mutant analysis, Specific Aim 2. Define the role of Spata7 in retinitis pigmentosa, Specific Aim 3. Determine the prevalence of SPATA7 mutations in ocular disease patients. Together these studies will greatly increase our understanding of the mechanisms of human retinal disease and improve our ability to diagnose, prevent, and treat LCA and other human ocular dystrophies. The main goal of this project is to create a model of the human retinal disease called Leber congenital amaurosis (LCA), which is the leading cause of blindness in infants. In order to create more effective means of diagnosis, prevention, and treatment, we need a more detailed understanding of this devastating disease. Our model for LCA using mouse gene targeting will provide an essential platform for determining the exact defects in the eye and to conduct gene therapy studies to correct such defects
Keywords: Accounting; Affect; Alleles; Allelomorphs; amaurosis congenita of Leber; Animal Model; Animal Models and Related Studies; base; Birth; Blindness; Cell/Tissue, Immunohistochemistry; Clinical; clinical phenotype; Collection; Complement; Complement Proteins; congenital amaurosis of retinal origin; congenital retinal blindness; congenital retinal blindness (CRB); congenital retinitis pigmentosa; Data; Defect; Diagnosis; Diagnostic Findings; Disease; disease-causing mutation; disease/disorder; Disorder; Drug Evaluation, Preclinical; Drug Screening; dysgenesis neuroepithelialis retinae; early onset; Electrophysiology; Electrophysiology (science); electroretinogram; Electroretinography; European; Evaluation Studies, Drug, Pre-Clinical; Evaluation Studies, Drug, Preclinical; Eye; Eyeball; Fundus; gene product; Gene Targeting; gene therapy; Gene Transfer Clinical; Gene Transfer Procedure; Gene-Tx; Genes; Genetic Alteration; Genetic Change; Genetic defect; Genetic Intervention; genetic therapy; genome mutation; Genotype; Goals; heavy metal lead; heavy metal Pb; Hereditary; hereditary epithelial dysplasia of retina; hereditary retinal aplasia; heredoretinopathia congenitalis; Heterogeneity; Histology; Homozygote; Human; Human, General; IHC; Immunohistochemistry; Immunohistochemistry Staining Method; improved; infancy; Infant; infantile; Inherited; Intervention, Genetic; Knockout Mice; Lead; Leber abiotrophy; Leber congenital amaurosis; Leber congenital amaurosis (LCA); Leber congenital tapetoretinal degeneration; Leber disease 2; Leber`s amaurosis; Leber`s congenital amaurosis; Leber`s disease; Life; Light; Mammals, Mice; Man (Taxonomy); Man, Modern; Mice; Mice, Knock-out; Mice, Knockout; Mice, Mutant Strains; model organism; Modeling; Molecular; Molecular Biology, Gene Therapy; Molecular Diagnosis; mouse model; mouse mutant; Murine; Mus; mutant; Mutant Strains Mice; Mutation; Names; Neurophysiology / Electrophysiology; novel; Null Mouse; nystagmus; Nystagmus, Pathologic; Parturition; Pathologic Nystagmus; Patients; Pb element; Phenotype; Photoradiation; Photoreceptor Cell; Photoreceptors; Photosensitive Cell; Pigmentary Retinopathy; Population; Preclinical Drug Evaluation; Prevalence; prevent; preventing; Prevention; Proteins; public health relevance; response; Retina; retina disease; retina disorder; Retinal Defect; Retinal Diseases; Retinal Disorder; Retinal Dystrophy; Retinitis Pigmentosa; retinopathy; Rod-Cone Dystrophy; Role; screening; Screening procedure; screenings; Signs and Symptoms; social role; subretinal injection; System; System, LOINC Axis 4; Tapetoretinal Degeneration; Targetings, Gene; TEM; Testing; Therapy, DNA; Transmission Electron Microscopy; Virus; Viruses, General; Visual; Visual Receptor; Weaning
Relevance: The main goal of this project is to create a model of the human retinal disease called Leber congenital amaurosis (LCA), which is the leading cause of blindness in infants. In order to create more effective means of diagnosis, prevention, and treatment, we need a more detailed understanding of this devastating disease. Our model for LCA using mouse gene targeting will provide an essential platform for determining the exact defects in the eye and to conduct gene therapy studies to correct such defects
Project start date: 2011-02-01
Project end date: 2015-01-31
Budget start date: 1-FEB-2011
Budget end date: 31-JAN-2012
PFA/PA: PA-10-067
1R01EY020540-01A1 (2011): $439740
GENOME-WIDE DISSECTION OF THE RETINAL DETERMINATION NETWORK
Chen Rui, Assistant Professor
Baylor College Of Medicinecity: Houston country: United States (us)
Grant 5R01EY016853-05 from National Eye Institute
Abstract: The goal of this research project is to identify, genome-wide, the genes and genetic networks controlling retinal cell development, which will form the basis for further studies designed to improve our ability to understand, diagnose, treat and prevent human retinal diseases. Using the fruit fly Drosophila melanogaster as an animal model system, genes and pathways regulated by eyeless (ey), a Pax6 homolog that functions near the top of the genetic hierarchy controlling retinal cell fate specification will be identified using a combinatorial approach of genetics, genomics, and computational biology. In addition, this novel combinatorial approach, once established, can be applied to studies of other transcription factors during retinal development. A Pax6 homolog, ey functions as a master control gene that is both essential and sufficient for eye development. However, only one direct target of ey, sine oculis (so), has been identified. As an essential step toward a full understanding of ey function, a genome-wide screen for its direct downstream targets using three independent methods will be conducted. Gene expression profiles as well as computational approaches have been used to identify several hundred novel gene candidates regulated by ey. To complement the first two approaches, chromatin profiling experiments will be conducted to identify Ey binding sites in the Drosophila genome. Further studies of direct downstream effectors of Ey, as well as other novel genes acting at different levels of the genetic hierarchy identified in this study, will provide us with a comprehensive understanding of the mechanisms of retinal development. Our Specific Aims are 1. Identification of direct downstream targets of Eyeless during Drosophila retinal development 2. Genome-wide identification of Ey binding sites in the Drosophila genome 3. Functional characterization of novel genes during Drosophila eye development Studies of genes identified in this study will provide the basis for a more complete understanding of eyeless function as well as mechanisms of eye development. Since both ey and many of its downstream genes are highly conserved in humans and many developmental parallels exist between Drosophila and mammalian retina, this work will directly impact our understanding of human retinal development
Keywords: Alleles; Allelomorphs; Animal Model; Animal Models and Related Studies; Anterior; Assay; base; Base Pairing; Binding; Binding (Molecular Function); Binding Sites; Bioassay; Biologic Assays; Biological Assay; Biological Models; Candidate Disease Gene; Candidate Gene; cell fate specification; Cells; Chimera Protein; Chimeric Proteins; ChIP (chromatin immunoprecipitation); CHIP assay; Chromatin; chromatin immunoprecipitation; combinatorial; Combining Site; comparative; Complement; Complement Proteins; Computational Biology; Consensus; Data; design; designing; Development; Diagnosis; DISSEC; Dissection; Drosophila; Drosophila eye; Drosophila genome; Drosophila genus; Drosophila melanogaster; Elements; Enhancers; experiment; experimental research; experimental study; Expression Profiling; Expression Signature; Eye; Eye Development; eye morphogenesis; Eyeball; Flies; fly; fruit fly; Fruit Fly, Drosophila; Fusion Protein; Gene Action Regulation; Gene Expression; Gene Expression Monitoring; Gene Expression Pattern Analysis; Gene Expression Profiling; Gene Expression Regulation; gene function; Gene Products, RNA; Gene Regulation; Gene Regulation Process; GeneHomolog; Genes; Genetic; genetic manipulation; Genetics, in situ Hybridization; Genome; Genome Scan; genome wide association scan; genome wide association studies; genome wide association study; genome, Drosophila; genome, fruit fly; genome-wide; genome-wide scan; genomewide association scan; genomewide association studies; genomewide association study; genomewide scan; Genomics; Germ-Line Mutation; Germline Mutation; Goals; GWAS; Hereditary Mutation; Homolog; Homologous Gene; Homologue; Human; Human, General; improved; In element; In Situ Hybridization; in situ Hybridization Staining Method; In Vitro; in vivo; Indium; interest; Investigators; Man (Taxonomy); Man, Modern; Methods; model organism; Model System; Models, Biologic; molecuar profile; Molecular Fingerprinting; Molecular Interaction; Molecular Profiling; molecular signature; mutant; novel; ocular development; Oligo; Oligonucleotides; pathway; Pathway interactions; Pattern; Phenotype; Post-Transcriptional Gene Silencing; Post-Transcriptional Gene Silencings; Posttranscriptional Gene Silencing; Posttranscriptional Gene Silencings; prevent; preventing; Process; Profilings, Gene Expression; Quelling; R01 Mechanism; R01 Program; Reactive Site; Research Design; Research Grants; Research Personnel; Research Project Grants; Research Projects; Research Projects, R-Series; research study; Researchers; Resolution; Retina; retina disease; retina disorder; Retinal; Retinal Diseases; Retinal Disorder; retinopathy; reverse transcriptase PCR; Reverse Transcriptase Polymerase Chain Reaction; Ribonucleic Acid; RNA; RNA Interference; RNA Silencing; RNA Silencings; RNA, Non-Polyadenylated; RNAi; RPG; RT-PCR; RTPCR; Sensitivity and Specificity; Sequence-Specific Posttranscriptional Gene Silencing; Site; Staging; study design; Study Type; System; System, LOINC Axis 4; Transcript Expression Analyses; Transcript Expression Analysis; transcription factor; transgenic; Transgenic Organisms; whole genome association studies; whole genome association study; Work
Project start date: 2005-08-01
Project end date: 2011-05-31
Budget start date: 1-JUN-2009
Budget end date: 31-MAY-2011
5R01EY016853-05 (2009): $291309