Determining Molecular Mechanisms of Human Glaucoma Genes

确定人类青光眼基因的分子机制

基本信息

项目摘要

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.
摘要

项目成果

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Kayarat Saidas Nair其他文献

Kayarat Saidas Nair的其他文献

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{{ truncateString('Kayarat Saidas Nair', 18)}}的其他基金

Diversity Supplement_Torres
多样性补充_托雷斯
  • 批准号:
    10674359
  • 财政年份:
    2022
  • 资助金额:
    $ 41.15万
  • 项目类别:
Characterizing the Molecular Mechanisms of PRSS56-Dependent Ocular Growth and Refractive Error
表征 PRSS56 依赖性眼生长和屈光不正的分子机制
  • 批准号:
    10705558
  • 财政年份:
    2022
  • 资助金额:
    $ 41.15万
  • 项目类别:
Characterizing the Molecular Mechanisms of PRSS56-Dependent Ocular Growth and Refractive Error
表征 PRSS56 依赖性眼生长和屈光不正的分子机制
  • 批准号:
    10367868
  • 财政年份:
    2022
  • 资助金额:
    $ 41.15万
  • 项目类别:
Determining Molecular Mechanisms of Human Glaucoma Genes
确定人类青光眼基因的分子机制
  • 批准号:
    10612930
  • 财政年份:
    2022
  • 资助金额:
    $ 41.15万
  • 项目类别:
Determining Molecular and Cellular Mechanisms of Glaucoma
确定青光眼的分子和细胞机制
  • 批准号:
    9211347
  • 财政年份:
    2014
  • 资助金额:
    $ 41.15万
  • 项目类别:
Determining Molecular and Cellular Mechanisms of Glaucoma
确定青光眼的分子和细胞机制
  • 批准号:
    8788029
  • 财政年份:
    2014
  • 资助金额:
    $ 41.15万
  • 项目类别:
Determining Molecular and Cellular Mechanisms of Glaucoma
确定青光眼的分子和细胞机制
  • 批准号:
    8784082
  • 财政年份:
    2014
  • 资助金额:
    $ 41.15万
  • 项目类别:
Determining Molecular and Cellular Mechanisms of Glaucoma
确定青光眼的分子和细胞机制
  • 批准号:
    9003054
  • 财政年份:
    2014
  • 资助金额:
    $ 41.15万
  • 项目类别:
Determining Molecular and Cellular Mechanisms of Glaucoma
确定青光眼的分子和细胞机制
  • 批准号:
    8418312
  • 财政年份:
    2013
  • 资助金额:
    $ 41.15万
  • 项目类别:
Morphology Core
形态核心
  • 批准号:
    10665568
  • 财政年份:
    1997
  • 资助金额:
    $ 41.15万
  • 项目类别:

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