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Principal Investigator: Kayarat Saidas Nair
Organization: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
Fiscal Year: 2024
Award: $417,936
Funding agency: National Eye Institute
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.
Terms: <Affect><Alleles><Allelomorphs><Aqueous Humor><Assay><Autoregulation><Basal Transcription Factor><Basal transcription factor genes><Binding Sites><Bioassay><Biological Assay><Biological Function><Biological Process><Biology><Blindness><Body Tissues><Bone-Derived Transforming Growth Factor><CRISPR><CRISPR/Cas system><Cell Adhesion><Cell Body><Cell Culture Techniques><Cell-Extracellular Matrix><Cells><Cellular Adhesion><ChIP Sequencing><ChIP-seq><ChIPseq><Clustered Regularly Interspaced Short Palindromic Repeats><Combining Site><Complex><Consensus><Cranial Nerve II Diseases><Cranial Nerve II Disorder><Cytoskeletal Modeling><Cytoskeletal Organization><Cytoskeletal Organization Process><Cytoskeletal Reorganization><DNA Binding><DNA Binding Interaction><DNA bound><Defect><Development><Dexamethasone><Disease><Disease Progression><Disorder><Drainage><Drainage procedure><Dysfunction><ECM><Enhancers><Exhibits><Extracellular Matrix><Extracellular Matrix Proteins><FKHL7><FOXC1><FOXC1 gene><FREAC3><Forkhead Box C1><Forkhead, Drosophila, Homolog-Like 7><Forkhead-Related Activator 3><Functional RNA><Functional disorder><Gene Action Regulation><Gene Expression><Gene Expression Regulation><Gene Regulation><Gene Regulation Process><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic><Genetic Transcription><Genomic approach><Genomics><Glaucoma><Goals><Heterozygote><Homeostasis><Human><Human Genetics><Impairment><Intervening Sequences><Intraocular Fluid><Intraocular Pressure><Introns><Maintenance><Mediating><Mice><Mice Mammals><Milk Growth Factor><Modeling><Modern Man><Molecular><Murine><Mus><Neural-Optical Lesion><Non-Coding><Non-Coding RNA><Non-translated RNA><Noncoding RNA><Nontranslated RNA><Nucleic Acid Regulator Regions><Nucleic Acid Regulatory Sequences><Ocular Tension><Optic Nerve Diseases><Optic Neuropathy><POAG><Pathogenesis><Pathway interactions><Persons><Physiologic Intraocular Pressure><Physiological Homeostasis><Physiopathology><Platelet Transforming Growth Factor><Play><Predisposition gene><Prevalence><Primary Open Angle Glaucoma><Promoter Regions><Promotor Regions><Public Health><RNA Expression><RNA Seq><RNA sequencing><RNAseq><Reactive Site><Regulation><Regulatory Regions><Reporter><Resistance><Risk Factors><Role><Schlemm's canal><Second Cranial Nerve Diseases><Structure of sinus venosus of sclera><Study models><Susceptibility Gene><System><TGF B><TGF-beta><TGF-β><TGFbeta><TGFβ><Testing><Tissues><Trabecular Meshwork><Trabecular meshwork structure><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><Transforming Growth Factor beta><Transforming Growth Factor-Beta Family Gene><Untranslated RNA><Variant><Variation><cell culture><cell cultures><chromatin immunoprecipitation-sequencing><developmental><functional genomics><genetic approach><genetic promoter element><genetic promoter sequence><genetic regulatory element><genetic strategy><genomic effort><genomic strategy><glaucomatous><heterozygosity><high intra-ocular pressure><high intraocular pressure><in vitro Assay><insight><intra-ocular pressure><lentiviral-mediated><mouse model><murine model><noncoding><optic nerve disorder><overexpress><overexpression><pathophysiology><pathway><predisposing gene><prevent><preventing><programs><promoter sequence><resistant><second cranial nerve disorder><social role><susceptibility allele><susceptibility locus><susceptibility variant><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic target><transcription factor><transcription regulatory network><transcriptome sequencing><transcriptomic sequencing><vision loss><visual loss>