Genetic Modulation of Glaucoma
青光眼的基因调控
基本信息
- 批准号:8269646
- 负责人:
- 金额:$ 37.49万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-06-01 至 2015-05-31
- 项目状态:已结题
- 来源:
- 关键词:AllelesAtrophicBioinformaticsBiological AssayBlindnessCandidate Disease GeneCell CountClinicalDataData SetDiseaseDisease modelEvaluationEyeEye diseasesGenesGeneticGenotypeGlaucomaHaplotypesHumanHuman ChromosomesInvestigationIrisIris DiseasesLaboratoriesLeadLinkLiteratureMapsMethodsMicroarray AnalysisMolecularMolecular ModelsMusMutationOpen-Angle GlaucomaOptic NerveOutcomeParentsPatientsPenetrancePhenotypePhysiologic Intraocular PressurePigmentsPredispositionQuantitative Trait LociReadingRecombinant Inbred StrainResearchResearch PersonnelResistanceRetinaSeveritiesSeverity of illnessStatistical ModelsSurveysTestingTranslationsVariantWhole-Genome Shotgun SequencingWorkage relatedauthoritycohortexpectationexperienceganglion cellmolecular modelingmutanttrait
项目摘要
In this proposal, we use our enlarged set of BXD recombinant inbred strains to identify gene loci that are
involved in modulating the severity of glaucoma. Our approach combines a thorough clinical and laboratory
examination, and microarray analysis of the entire set of 81 BXD lines generated over the last 10 years with the
express purpose of studying the genetics of eye disease and glaucoma. One of the parental strains of BXD,
DBA/2J, develop an age-related glaucoma that is preceded by iris atrophy and pigment dispersion. While
mutant alleles of two genes, Tryp1 and Gpnmb, cause the iris disease in D2, the literature strongly suggests that
these mutations are not sufficient to cause glaucoma. Specifically, introgression of both mutant alleles onto
C57BL/6J, the other parent strain of BXD, results in a marked resistance to optic nerve damage. This indicates
that genes other than those that cause pigment dispersion influence the glaucomatous phenotype. The current
proposal describes a unique opportunity to define the modifying loci. In Aim 1, we test the hypothesis that the
combined mutations in Tryp1 and Gpnmb are not sufficient to cause all aspects of the glaucoma phenotype. If
our hypothesis is true, we expect to see that the severity of disease is not solely dependent on the two mutant
alleles. We have already identified multiple BXD strains in which IOP and genetic diplotype are not correlated.
As we systematically examine all BXD strains and establish relations between phenotype and diplotype, we
fully expect to find additional strains that defy expectations of a simple two-locus disease model. In Aim 2, we
define loci and genes that modulate glaucoma severity. To do so, we will identify and evaluate candidate
genes within loci that modulate the severity of the glaucoma phenotype. We will exploit our new whole
genome shotgun sequence for D2 (about >50x short read coverage generated at UTHSC in 2009) along with
massive whole eye and whole retina expression datasets that we have also generated as a prelude to this work.
We expect to efficiently nominate and evaluate candidate glaucoma genes using state-of-the-art bioinformatic
methods and conventional molecular assays. In Aim 3, we use bidirectional translation. We test the
translational validity of mouse candidates from Aim 2 using cohorts of human glaucoma patients. Dr. J. Wiggs
and colleagues will perform focused gene association studies using candidate glaucoma genes nominated in
Aim 2. Specifically, we use association analyses of markers encompassing syntenic regions of human
chromosomes. In reciprocal reverse translation, we (MMJ and LL) will evaluate known, new, and candidate
glaucoma genes from clinical cohorts and determine if and how these variants are associated with glaucoma-
associated traits in BXDs. Combining the top priority gene candidates from both mouse and human glaucoma
studies, we will generate molecular and statistical models of susceptibility candidate genes, linked
phenotypes, and associated mechanisms.
在这个建议中,我们使用我们的扩大的BXD重组自交系来鉴定基因位点
项目成果
期刊论文数量(0)
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MONICA M JABLONSKI其他文献
MONICA M JABLONSKI的其他文献
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{{ truncateString('MONICA M JABLONSKI', 18)}}的其他基金
Novel Extended Release Glaucoma Therapy for Once Daily Dosing
每日一次给药的新型青光眼缓释疗法
- 批准号:
9912475 - 财政年份:2020
- 资助金额:
$ 37.49万 - 项目类别:
Novel Extended Release Glaucoma Therapy for Once Daily Dosing
每日一次给药的新型青光眼缓释疗法
- 批准号:
10374760 - 财政年份:2020
- 资助金额:
$ 37.49万 - 项目类别:
Novel Extended Release Glaucoma Therapy for Once Daily Dosing
每日一次给药的新型青光眼缓释疗法
- 批准号:
10597097 - 财政年份:2020
- 资助金额:
$ 37.49万 - 项目类别:
Novel Extended Release Glaucoma Therapy for Once Daily Dosing
每日一次给药的新型青光眼缓释疗法
- 批准号:
10542485 - 财政年份:2020
- 资助金额:
$ 37.49万 - 项目类别:
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