Validating novel candidate genes for normal-tension glaucoma
验证正常眼压性青光眼的新候选基因
基本信息
- 批准号:10749126
- 负责人:
- 金额:$ 4.08万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-01 至 2025-08-30
- 项目状态:未结题
- 来源:
- 关键词:12q13ATP phosphohydrolaseAdultAffectBiological AssayBlindnessBloodBlood specimenCandidate Disease GeneCellsChromosomesClassificationCo-ImmunoprecipitationsCodeCouplingDataDatabasesDefectDiagnosisDiseaseDisease ProgressionEarly treatmentElectrostaticsEscherichia coliExtracellular MatrixExtracellular Matrix ProteinsFamilyFamily memberFunctional disorderFutureGene ExpressionGene Expression ProfilingGene MutationGenesGeneticGenetic DiseasesGenomicsGlaucomaGoalsHeat-Shock Proteins 90HeritabilityImpairmentIn VitroIndividualLinkMaintenanceMendelian disorderMethodsMissense MutationModelingMolecularMolecular ChaperonesMutationN-terminalNormal RangeNucleotidesOptic AtrophyOptic NervePathogenesisPathogenicityPathway interactionsPatientsPhysiologic Intraocular PressurePopulationPositioning AttributePrevalenceProductionProteinsRNA Polymerase IIRecording of previous eventsRegulationRiskRisk FactorsRoleRunningScaffolding ProteinScientistStructureTertiary Protein StructureTestingTherapeuticTissue-Specific Gene ExpressionVariantautosomebiobankcareercohortearly screeningexomeexperimental studygene discoverygene functiongenetic pedigreegenetic variantgenome analysisgenome sequencinggenome wide association studyhuman diseaseimprovedin silicomembermodifiable riskmolecular diagnosticsmutantnovelnovel therapeuticsoptic nerve disorderprotein protein interactionrare variantretinal ganglion cell degenerationrisk variantscaffoldscreeningsegregationskillstraditional therapytranscriptome sequencingwhole genome
项目摘要
ABSTRACT
My ultimate career goal is to become an independent scientist researching the genetic mechanisms
of Mendelian disorders in hopes of improving patient therapeutics. Specifically, I am focused on disease
gene discovery in familial cohorts, which remains one of the most effective means by which to study normal-
tension glaucoma (NTG). Glaucoma describes a group of ocular conditions characterized by the
progressive degeneration of the retinal ganglion cells (RGCs) that comprise the optic nerve and is present
in 1-3% of the adult population. Traditional therapies have focused on lowering intraocular pressure
(IOP), the largest modifiable risk factor. However, a subset of individuals with NTG – a diagnosis which
accounts for nearly one-third of all glaucoma cases and denotes optic atrophy despite an IOP that is within
normal range – continue to show disease progression after IOP-lowering treatment. A critical barrier to
developing new treatments is understanding the molecular pathogenesis of NTG. To this end, our group
identified a pedigree with autosomal dominant NTG that is poorly responsive to IOP-lowering therapy.
Linkage, whole-exome, and whole-genome analyses revealed that there is likely more than one risk allele
of high effect segregating in individual family members, though the vast majority of cases seem to be
explained by a very rare missense substitution at a highly conserved residue in scaffolding/chaperone
protein RPAP3. This variant, with high in silico pathogenicity scores, is predicted to disrupt the N-terminal
domain of the protein. The N-terminal domain is critical for stimulating the ATPase activity of HSP90,
another scaffolding/chaperone protein that modulates the production of extracellular matrix (ECM)
components. Further, RNA-seq from familial blood samples revealed that ECM-associated genes were
among the most dysregulated in a differential gene expression analysis. These observations support
the hypothesis that disruptions in the N-terminus of RPAP3 impair HSP90 regulation, leading to defects
in ECM production/maintenance. This could result in normal-tension glaucoma by compromising key
optic nerve-supporting structures like the lamina cribrosa. My proposal seeks to: (i) determine the functional
consequences of RPAP3 coding variants on HSP90 interaction/stimulation and ECM gene expression,
(ii) determine the prevalence of deleterious RPAP3 variants in a cohort of patients diagnosed with glaucoma,
and (iii) elucidate additional glaucoma risk variants segregating in this large family. The results may lead to
improved screening and treatment options for NTG patients. By carrying out these aims, I will also
broaden my skillset in disease gene discovery and functional characterization of genetic variants, poising me
for a career focused on human disease genetics and molecular diagnostics.
摘要
项目成果
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