Diversity Supplement_Torres
Diversity Supplement_Torres
批准号:
10674359
负责人:
Kayarat Saidas Nair
金额:
$4.75万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-05-01 至 2026-03-31
关键词:
AffectAllelesAqueous HumorBinding SitesBiological AssayBiological ProcessBiologyBlindnessCell AdhesionCell Culture TechniquesCellsChIP-seqClustered Regularly Interspaced Short Palindromic RepeatsComplexConsensusCytoskeletal ModelingDNA BindingDefectDevelopmentDexamethasoneDiseaseDisease ProgressionDrainage procedureEnhancersExhibitsExtracellular MatrixExtracellular Matrix ProteinsFOXC1 geneFunctional disorderGene ExpressionGene Expression RegulationGenesGeneticGenetic TranscriptionGenomic approachGenomicsGlaucomaGoalsHeterozygoteHomeostasisHumanHuman GeneticsImpairmentIntronsLeadMaintenanceMediatingModelingMolecularMusNucleic Acid Regulatory SequencesPathogenesisPathway interactionsPersonsPhysiologic Intraocular PressurePlayPrevalencePrimary Open Angle GlaucomaPromoter RegionsPublic HealthRegulationRegulator GenesReporterResistanceRisk FactorsRoleStructure of sinus venosus of scleraStudy modelsSusceptibility GeneSystemTestingTissuesTrabecular meshwork structureUntranslated RNAVariantbasefunctional genomicsgenetic approachhigh intraocular pressurein vitro Assayinsightlentiviral-mediatedmouse modeloptic nerve disorderoverexpressionpreventprogramstargeted treatmenttherapeutic targettranscription factortranscription regulatory networktranscriptome sequencing
中文摘要
摘要
青光眼是世界范围内致盲的主要原因,是一个重大的公共卫生问题。在美国,它影响
270多万人,到2050年,其流行率将上升到730万。需要有针对性的治疗,
预防青光眼或减缓其进展。一个主要的风险因素是高眼内压(IOP),通常是由于
房水流出受损。然而,所涉及的基因和途径知之甚少。
我们已经鉴定了编码转录因子GLIS 1的GLIS 1作为原发性开放性乳腺癌的易感基因。
角型青光眼(POAG),并显示Glis 1-/-小鼠具有青光眼的病理生理学特征。我们
还发现Glis 1主要在小梁网(TM)中表达,这是骨小梁的关键组成部分。
眼引流组织调节AqH流出,Glis 1-/-小鼠表现出进行性TM变性,
导致高眼压和青光眼性视神经病变-突出了该模型用于研究的相关性
青光眼我们初步的功能基因组分析表明,GLIS 1与GLIS 3相互作用,
FOXC 1是先前与IOP升高有关的转录因子,用于调节TM细胞中的基因表达。
此外,降低或增加GLIS 1活性可损害眼引流组织的完整性。使用唯一
小鼠模型,遗传和功能基因组方法,以及体外试验,我们建议表征
GLIS 1依赖性转录调控网络及其在稳态和功能障碍中作用
眼部引流组织在目标1中,我们将检验GLIS 1表达增加有助于
POAG相关的眼引流组织缺损,并确定POAG相关的变异是否
在GLIS 1增强子区域中鉴定的其在原代人TM细胞中的转录活性增加。我们将
还测试了小鼠TM中GLIS 1过表达是否导致高IOP和眼引流组织缺陷
类似于POAG。最后,我们将评估地塞米松和TGFβ2的潜在作用,
作为GLIS 1的上游调节因子参与IOP升高。在目标2中,我们将测试潜在的遗传
Glis 1和Foxc 1和/或Glis 3在眼引流组织稳态中的相互作用。我们将确定
Glis 1和Foxc 1或Glis 1和Glis 3的无效等位基因杂合的小鼠是否发生TM缺陷,
改变IOP调节。同时,我们将描述转录程序和分子途径
与TM的维持和功能有关。这些研究将提供重要的机制洞察眼
引流组织稳态和功能障碍,并可能揭示治疗青光眼的目标。
英文摘要
ABSTRACT
Glaucoma, a major cause of blindness worldwide, is a significant public health concern. In the U.S., it affects
over 2.7 million people and its prevalence will rise to 7.3 million by 2050. Targeted therapies are needed to
prevent glaucoma or slow its progression. A major risk factor is high intraocular pressure (IOP), typically due to
impaired aqueous humor (AqH) outflow. However, the genes and pathways involved are poorly understood.
We have identified GLIS1, encoding the transcription factor GLIS1, as a susceptibility gene for primary open-
angle glaucoma (POAG) and showed that Glis1–/– mice have pathophysiological hallmarks of glaucoma. We
also found that Glis1 is predominantly expressed in the trabecular meshwork (TM), a key component of the
ocular drainage tissue regulating AqH outflow, and that Glis1–/– mice exhibit progressive TM degeneration,
leading to high IOP, and glaucomatous optic neuropathy—highlighting the relevance of this model for studies
of glaucoma. Our preliminary functional genomic analysis suggested that GLIS1 interacts with GLIS3 and
FOXC1, transcription factors previously implicated in elevated IOP, to regulate gene expression in TM cells.
Moreover, reduced or increased GLIS1 activity can impair the integrity of ocular drainage tissues. Using unique
mouse models, genetic and functional genomic approaches, and in vitro assays, we propose to characterize
the GLIS1-dependent transcriptional regulatory network and determine its role in homeostasis and dysfunction
of ocular drainage tissue. In Aim 1, we will test the hypothesis that increased GLIS1 expression contributes to
POAG-associated ocular drainage tissue defects and determine whether the POAG-associated variants we
identified in GLIS1 enhancer regions increased its transcriptional activity in primary human TM cells. We will
also test whether GLIS1 overexpression in the mouse TM leads to high IOP and ocular drainage tissue defects
similar to those in POAG. Finally, we will assess the potential role of dexamethasone and TGFβ2, previously
implicated in IOP elevation, as upstream regulators of GLIS1. In Aim 2, we will test for potential genetic
interactions between Glis1 and Foxc1 and/or Glis3 in ocular drainage tissue homeostasis. We will determine
whether mice heterozygous for null alleles of both Glis1 and Foxc1 or Glis1 and Glis3 develop TM defects and
altered IOP regulation. In parallel, we will characterize the transcriptional program and molecular pathways
implicated in TM maintenance and function. These studies will provide important mechanistic insight into ocular
drainage tissue homeostasis and dysfunction and could reveal targets for therapies to manage glaucoma.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Characterizing the Molecular Mechanisms of PRSS56-Dependent Ocular Growth and Refractive Error
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批准号:10705558
-
项目类别:
-
资助金额:$39.94万
-
财政年份:2022
-
负责人:Kayarat Saidas Nair
-
依托单位:
Characterizing the Molecular Mechanisms of PRSS56-Dependent Ocular Growth and Refractive Error
-
批准号:10367868
-
项目类别:
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资助金额:$40.38万
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财政年份:2022
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负责人:Kayarat Saidas Nair
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依托单位:
Determining Molecular Mechanisms of Human Glaucoma Genes
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批准号:10444972
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项目类别:
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资助金额:$41.15万
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财政年份:2022
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负责人:Kayarat Saidas Nair
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依托单位:
Determining Molecular Mechanisms of Human Glaucoma Genes
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批准号:10612930
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项目类别:
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资助金额:$38.13万
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财政年份:2022
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负责人:Kayarat Saidas Nair
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依托单位:
Determining Molecular and Cellular Mechanisms of Glaucoma
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批准号:9211347
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项目类别:
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资助金额:$39.63万
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财政年份:2014
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负责人:Kayarat Saidas Nair
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依托单位:
Determining Molecular and Cellular Mechanisms of Glaucoma
-
批准号:8788029
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项目类别:
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资助金额:$38.78万
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财政年份:2014
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负责人:Kayarat Saidas Nair
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依托单位:
Determining Molecular and Cellular Mechanisms of Glaucoma
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批准号:8784082
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项目类别:
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资助金额:$38.61万
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财政年份:2014
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负责人:Kayarat Saidas Nair
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依托单位:
Determining Molecular and Cellular Mechanisms of Glaucoma
-
批准号:9003054
-
项目类别:
-
资助金额:$39.63万
-
财政年份:2014
-
负责人:Kayarat Saidas Nair
-
依托单位:
Determining Molecular and Cellular Mechanisms of Glaucoma
-
批准号:8418312
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项目类别:
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资助金额:$45.14万
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财政年份:2013
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负责人:Kayarat Saidas Nair
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依托单位:
Morphology Core
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批准号:10665568
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项目类别:
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资助金额:$31.93万
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财政年份:1997
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负责人:Kayarat Saidas Nair
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依托单位:
Morphology Core
-
批准号:10426213
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项目类别:
-
资助金额:$31.93万
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财政年份:1997
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负责人:Kayarat Saidas Nair
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依托单位:
Morphology Core
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批准号:10203972
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项目类别:
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资助金额:$37.41万
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财政年份:1997
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负责人:Kayarat Saidas Nair
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依托单位:
Morphology Core
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批准号:9795337
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项目类别:
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资助金额:$34.4万
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财政年份:--
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负责人:Kayarat Saidas Nair
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依托单位:
Morphology Core
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批准号:10017977
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项目类别:
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资助金额:$40.32万
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财政年份:--
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负责人:Kayarat Saidas Nair
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依托单位:
海外基金