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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

批准号：
10444972
负责人：
Kayarat Saidas Nair
金额：
$ 41.15万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10444972
关键词：
Affect Alleles Aqueous Humor Binding Sites Biological Assay Biological Process Biology Blindness Cell Adhesion Cell Culture Techniques Cells ChIP-seq Clustered Regularly Interspaced Short Palindromic Repeats Complex Consensus Cytoskeletal Modeling DNA Binding Defect Development Dexamethasone Disease Disease Progression Drainage procedure Enhancers Exhibits Extracellular Matrix Extracellular Matrix Proteins FOXC1 gene Functional disorder Gene Expression Gene Expression Regulation Genes Genetic Genetic Transcription Genomic approach Genomics Glaucoma Goals Heterozygote Homeostasis Human Human Genetics Impairment Introns Lead Maintenance Mediating Modeling Molecular Mus Nucleic Acid Regulatory Sequences Pathogenesis Pathway interactions Persons Physiologic Intraocular Pressure Play Prevalence Primary Open Angle Glaucoma Promoter Regions Public Health Regulation Regulator Genes Reporter Resistance Risk Factors Role Structure of sinus venosus of sclera Study models Susceptibility Gene System Testing Tissues Trabecular meshwork structure Untranslated RNA Variant base functional genomics genetic approach high intraocular pressure in vitro Assay insight lentiviral-mediated mouse model optic nerve disorder overexpression prevent programs targeted treatment therapeutic target transcription factor transcription regulatory network transcriptome sequencing

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