Models, mechanisms and treatment of LMX1B-induced glaucoma
LMX1B诱发青光眼的模型、机制和治疗
基本信息
- 批准号:10615130
- 负责人:
- 金额:$ 59万
- 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:2021-07-01 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAdvanced DevelopmentAffectAgeAgingAllelesAnterior segment dysgenesisAqueous HumorBinding ProteinsBiological AssayCell physiologyCellsChIP-seqCicatrixClustered Regularly Interspaced Short Palindromic RepeatsCo-ImmunoprecipitationsCollectionCommunitiesDNA BindingDataDefectDevelopmentDiseaseDominant-Negative MutationDrainage procedureEnergy MetabolismEthylnitrosoureaEventGenesGenetic TranscriptionGlaucomaGoalsHealthHumanIndividualInduced MutationInheritedLIM DomainLearningMetabolicMetabolismMethodsMitochondriaModelingMolecularMorphologyMusMutagenesisMutant Strains MiceMutationNail-Patella SyndromeNatureNiacinamideOpen-Angle GlaucomaOperative Surgical ProceduresOral AdministrationOxidative StressPathway interactionsPatientsPersonsPharmaceutical PreparationsPhenotypePhysiologic Intraocular PressurePhysiologicalPositioning AttributePredispositionPrimary Open Angle GlaucomaProcessProtein TruncationProteinsResistanceRisk FactorsRoleSeverity of illnessSpecificityStressStructureStructure of sinus venosus of scleraTestingTimeTissuesTrabecular meshwork structureTranscriptional RegulationVariantWorkcell typecellular resiliencedietarydominant genetic mutationearly onsetexperimental studyextracellulargenome-wide analysishigh intraocular pressurehomeodomainlimbalmitochondrial dysfunctionmitochondrial metabolismmutantnovelnovel therapeutic interventionpreventprotein functionprotein protein interactionrational designresiliencesingle cell sequencingtime intervaltooltranscription factortranscriptometranscriptomics
项目摘要
High intraocular pressure (IOP) is a major causal risk factor for glaucoma and is the target of all
current glaucoma therapies. Although the importance of the LMX1B genes in human primary
open-angle glaucoma (POAG) has clearly been demonstrated, the mechanisms by which
LMX1B mutations induce IOP elevation and glaucoma are not known. This project investigates
the molecular mechanism by which abnormalities in LMX1B impact IOP and contribute to
glaucoma. It will generate a more sophisticated understanding of a human glaucoma gene,
ultimately guiding new treatments. Additionally, it will provide well characterized LMX1B
glaucoma models to the community. Current IOP-lowering drugs are not effective in many
patients, and reduce IOP by no more than 25-30%. Surgery to provide new aqueous humor
(AQH) outlets often fails due to scar formation. Therefore, new IOP-lowering therapies are a
critical need. New pathways and candidate molecules must be identified to advance
development of more potent and specific anti-glaucoma targets. The specific nature of an
inherited LMX1B variant is suggested to contribute to differences in glaucoma subtype and
disease severity between individuals. We hypothesize that various LMX1B mutations have
differential mechanistic effects - affecting LMX1B function or the function of other proteins that
interact with LMX1B to regulate transcriptional activity/specificity. Our preliminary data support
this hypothesis. We will test our hypothesis in the following aims: Aim 1) Determine the impact
of selected Lmx1b mutations on phenotype and protein stability/function. Aim 2): Determine the
molecular mechanism by which Lmx1b mutations impact IOP. Aim 3) Determine if Lmx1b
impacts cellular metabolism and test a resilience boosting treatment.
高眼压是青光眼的主要致病危险因素,也是所有青光眼的目标。
目前青光眼的治疗方法。尽管Lmx1b基因在人类原发疾病中的重要性
开角型青光眼(POAG)已被明确证实,其发病机制
Lmx1b基因突变导致眼压升高,青光眼尚不清楚。这个项目调查了
Lmx1b基因异常影响眼压并导致眼压升高的分子机制
青光眼。它将产生对人类青光眼基因的更复杂的理解,
最终指导新的治疗方法。此外,它还将提供具有良好特性的Lmx1b
把青光眼模特带到社区。目前的降眼压药物在许多情况下并不有效
患者,眼压下降不超过25%-30%。手术提供新的房水
(AQH)插座经常因疤痕形成而失效。因此,新的降眼压疗法是一种
迫切需要。必须确定新的途径和候选分子才能推进
开发更有效和更特异的抗青光眼靶点。一种特定性质的
遗传的Lmx1b变异被认为是青光眼亚型和
个体之间的疾病严重程度。我们假设不同的Lmx1b突变
不同的机制效应-影响Lmx1b的功能或其他蛋白质的功能
与Lmx1b相互作用,调节转录活性/特异性。我们的初步数据支持
这个假说。我们将在以下目标中检验我们的假设:目标1)确定影响
选择Lmx1b突变对表型和蛋白质稳定性/功能的影响。目标2):确定
Lmx1b突变影响眼压的分子机制目标3)确定Lmx1b
影响细胞新陈代谢并测试增强复原力的治疗方法。
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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{{ truncateString('SIMON W JOHN', 18)}}的其他基金
Does VECAD at Schlemm canal cell-junctions determine IOP and glaucoma risk?
施莱姆管细胞连接处的 VECAD 是否可以确定 IOP 和青光眼风险?
- 批准号:
10096663 - 财政年份:2021
- 资助金额:
$ 59万 - 项目类别:
Models, mechanisms and treatment of LMX1B-induced glaucoma
LMX1B诱发青光眼的模型、机制和治疗
- 批准号:
10427201 - 财政年份:2021
- 资助金额:
$ 59万 - 项目类别:
Does VECAD at Schlemm canal cell-junctions determine IOP and glaucoma risk?
施莱姆管细胞连接处的 VECAD 是否可以确定 IOP 和青光眼风险?
- 批准号:
10534248 - 财政年份:2021
- 资助金额:
$ 59万 - 项目类别:
Does VECAD at Schlemm canal cell-junctions determine IOP and glaucoma risk?
施莱姆管细胞连接处的 VECAD 是否可以确定 IOP 和青光眼风险?
- 批准号:
10319958 - 财政年份:2021
- 资助金额:
$ 59万 - 项目类别:
Models, mechanisms and treatment of LMX1B-induced glaucoma
LMX1B诱发青光眼的模型、机制和治疗
- 批准号:
10184896 - 财政年份:2021
- 资助金额:
$ 59万 - 项目类别:
Cell Death Pathways in Glaucomatous Neurodegeneration
青光眼神经变性中的细胞死亡途径
- 批准号:
10663230 - 财政年份:2008
- 资助金额:
$ 59万 - 项目类别:
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