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?
基本信息
- 批准号:10534248
- 负责人:
- 金额:$ 71.17万
- 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:2021-01-01 至 2025-11-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAdherens JunctionAffectAntibodiesApicalAqueous HumorBiochemicalBiological ModelsBiologyBiomechanicsBlood VesselsClustered Regularly Interspaced Short Palindromic RepeatsComplexCytoplasmic TailDataDrainage procedureElectron MicroscopyEndothelial CellsEndotheliumEventExposure toGenesGeneticGlaucomaGoalsHumanImmunofluorescence ImmunologicIndividualIntercellular JunctionsKnock-in MouseKnock-outKnowledgeLabelLentivirusLiquid substanceLoxP-flanked alleleLymphatic Endothelial CellsMeasuresMediatingModelingMolecularMolecular ProfilingMusMutant Strains MiceMutatePECAM1 genePathologyPathway interactionsPermeabilityPharmaceutical PreparationsPhenylalaninePhosphoproteinsPhosphorylationPhysiologic Intraocular PressurePositioning AttributePrimary Open Angle GlaucomaProcessPropertyProteinsRegulationResistanceResolutionRiskRisk FactorsRoleSignal TransductionSignaling MoleculeSiteStructure of sinus venosus of scleraStudy modelsTestingTracerTranslatingTyrosineTyrosine Phosphorylationaqueous humor flowcadherin 5confocal imaginghigh intraocular pressureimprovedin vivoinnovationknockout genelight microscopymechanical forcemechanotransductionmutantnew technologynovelnovel therapeutic interventionpressurepreventprotein complexrational designresponsesensorshear stresstool
项目摘要
High IOP is a major causal risk factor for glaucoma and is the target of all current glaucoma
therapies. This project investigates pathways that control intraocular pressure. Abnormalities in
these pathways contribute to glaucoma. By characterizing pathways that control IOP using
mutant mice, we expect to better understand glaucoma risk at a molecular level and will provide
important new models for studying IOP and glaucoma. Characterization of important regulatory
models will improve understanding and ultimately guide new treatments. New and more
effective IOP-lowering treatments are needed. In glaucoma, elevated IOP results from
increased resistance to aqueous humor (AQH) drainage at the inner wall of Schlemm’s canal
(SC). The inner- wall endothelial cells of SC (SECs) are the final barrier to AQH exit into the
ocular vasculature and are critical in controlling AQH outflow. Approved medications do not
directly target the inner wall or the fundamental pathology that increases outflow resistance in
glaucoma. To correct this, greater knowledge of SC biology is required and we will assess the
role of mechanotransduction in determining IOP. Abnormal mechanotransduction may result in
elevated IOP and glaucoma. A central player in endothelial mechanotransduction is the
adherens junction complex (AJC) of which VECADHERIN (VECAD) is a critical protein.
Although SECs express VECAD and AJC proteins, the role of these proteins in determining
AQH outflow is not yet demonstrated. We will test the hypothesis that the VECAD is required for
AJC mechanotransduction in SECs, controlling AQH outflow and IOP. Our preliminary data
support this hypothesis. We will test our hypothesis in the following aims: Aim 1) Determine if
AJC protein phosphorylation/ signaling adaptively responds to IOP changes in vivo. Aim 2):
Determine the role of VECAD in regulating IOP in vivo. Studying mice with mutant version of
VECAD will provide key information about its functions and may provide valuable new models of
glaucoma. Aim 3) Determine the role of phosphorylation of specific tyrosine residues in VECAD
in IOP regulation. We will assess the roles of key tyrosines in vivo by using mutant mice where
individual tyrosine residues have been mutated to phenylalanine.
高IOP是青光眼的一个主要因果风险因素,也是当前所有青光眼的目标
治疗该项目研究控制眼内压的途径。异常
这些途径导致青光眼。通过表征控制IOP的途径,
突变小鼠,我们期望在分子水平上更好地了解青光眼风险,并将提供
研究IOP和青光眼的重要新模型。重要监管机构的特征
模型将提高理解,并最终指导新的治疗方法。新的和更
需要有效的降低IOP的治疗。在青光眼中,IOP升高是由于
施累姆氏管内壁的房水(AQH)引流阻力增加
(SC)。SC的内壁内皮细胞(SECs)是AQH进入SC的最后屏障。
眼血管系统,并在控制AQH流出的关键。批准的药物不
直接靶向内壁或增加流出阻力的基本病理,
青光眼为了纠正这一点,需要更多的SC生物学知识,我们将评估
机械传导在确定IOP中的作用。异常的机械传导可能导致
眼压升高和青光眼内皮机械转导中的中心参与者是
粘附连接复合物(AJC),其中VECADHERIN(VECAD)是一种关键蛋白。
尽管SEC表达VECAD和AJC蛋白,但这些蛋白在决定SEC的表达中的作用是不确定的。
AQH流出尚未得到证实。我们将检验以下假设:
SEC中的AJC机械转导,控制AQH流出和IOP。我们的初步数据
支持这一假设。我们将在以下目标中测试我们的假设:目标1)确定是否
AJC蛋白磷酸化/信号转导适应性地响应体内IOP变化。目标2):
确定VECAD在体内调节IOP中的作用。研究携带突变型
VECAD将提供有关其功能的关键信息,并可能提供有价值的新模型,
青光眼目的3)确定VECAD中特定酪氨酸残基的磷酸化作用
眼压调节。我们将通过使用突变小鼠来评估关键酪氨酸在体内的作用,
单个酪氨酸残基突变为苯丙氨酸。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
SIMON W JOHN其他文献
SIMON W JOHN的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
$ 71.17万 - 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:
$ 71.17万 - 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:
$ 71.17万 - 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:
$ 71.17万 - 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:
10615130 - 财政年份:2021
- 资助金额:
$ 71.17万 - 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:
$ 71.17万 - 项目类别:
相似海外基金
Oral pathogen - mediated pro-tumorigenic transformation through disruption of an Adherens Junction - associated RNAi machinery
通过破坏粘附连接相关的 RNAi 机制,口腔病原体介导促肿瘤转化
- 批准号:
10752248 - 财政年份:2024
- 资助金额:
$ 71.17万 - 项目类别:
Adherens junction dynamics and function in epithelial tissue morphogenesis
粘附连接动力学和上皮组织形态发生中的功能
- 批准号:
469118 - 财政年份:2022
- 资助金额:
$ 71.17万 - 项目类别:
Operating Grants
Adherens Junction dysfunction in Hidradenitis Suppurativa
化脓性汗腺炎的粘附连接功能障碍
- 批准号:
10701323 - 财政年份:2022
- 资助金额:
$ 71.17万 - 项目类别:
Adherens junction proteins in neuron-glia interactions
神经元-胶质细胞相互作用中的粘附连接蛋白
- 批准号:
9978138 - 财政年份:2019
- 资助金额:
$ 71.17万 - 项目类别:
Elucidation of the function of Focal adherens junction in morphogenesis
阐明焦点粘附连接在形态发生中的功能
- 批准号:
19K16145 - 财政年份:2019
- 资助金额:
$ 71.17万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Identifying and characterizing the effect of Aip1 on adherens junction remodeling in Drosophila follicular epithelium
鉴定和表征 Aip1 对果蝇滤泡上皮粘附连接重塑的影响
- 批准号:
528450-2018 - 财政年份:2018
- 资助金额:
$ 71.17万 - 项目类别:
Alexander Graham Bell Canada Graduate Scholarships - Master's
Src-mediated pathways regulating adherens junction assembly.
Src 介导的途径调节粘附连接组装。
- 批准号:
10166863 - 财政年份:2017
- 资助金额:
$ 71.17万 - 项目类别:
Src-mediated pathways regulating adherens junction assembly.
Src 介导的途径调节粘附连接组装。
- 批准号:
9310733 - 财政年份:2017
- 资助金额:
$ 71.17万 - 项目类别:
The function and interaction of focal adhesion and adherens junction in bone mechanosensing and mechanotransduction.
粘着斑和粘附连接在骨力传感和力转导中的功能和相互作用。
- 批准号:
17K17307 - 财政年份:2017
- 资助金额:
$ 71.17万 - 项目类别:
Grant-in-Aid for Young Scientists (B)
a-catenin and its binding partners in adherens junction assembly and function
α-连环蛋白及其在粘附连接组装和功能中的结合伙伴
- 批准号:
357714 - 财政年份:2016
- 资助金额:
$ 71.17万 - 项目类别:
Operating Grants