Models, mechanisms and treatment of LMX1B-induced glaucoma

LMX1B诱发青光眼的模型、机制和治疗

基本信息

批准号：
10615130
负责人：
SIMON W JOHN
金额：
$ 59万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
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：
2021-07-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10615130
关键词：
Address Advanced Development Affect Age Aging Alleles Anterior segment dysgenesis Aqueous Humor Binding Proteins Biological Assay Cell physiology Cells ChIP-seq Cicatrix Clustered Regularly Interspaced Short Palindromic Repeats Co-Immunoprecipitations Collection Communities DNA Binding Data Defect Development Disease Dominant-Negative Mutation Drainage procedure Energy Metabolism Ethylnitrosourea Event Genes Genetic Transcription Glaucoma Goals Health Human Individual Induced Mutation Inherited LIM Domain Learning Metabolic Metabolism Methods Mitochondria Modeling Molecular Morphology Mus Mutagenesis Mutant Strains Mice Mutation Nail-Patella Syndrome Nature Niacinamide Open-Angle Glaucoma Operative Surgical Procedures Oral Administration Oxidative Stress Pathway interactions Patients Persons Pharmaceutical Preparations Phenotype Physiologic Intraocular Pressure Physiological Positioning Attribute Predisposition Primary Open Angle Glaucoma Process Protein Truncation Proteins Resistance Risk Factors Role Severity of illness Specificity Stress Structure Structure of sinus venosus of sclera Testing Time Tissues Trabecular meshwork structure Transcriptional Regulation Variant Work cell type cellular resilience dietary dominant genetic mutation early onset experimental study extracellular genome-wide analysis high intraocular pressure homeodomain limbal mitochondrial dysfunction mitochondrial metabolism mutant novel novel therapeutic intervention prevent protein function protein protein interaction rational design resilience single cell sequencing time interval tool transcription factor transcriptome transcriptomics

项目摘要

High intraocular pressure (IOP) is a major causal risk factor for glaucoma and is the target of all current glaucoma therapies. Although the importance of the LMX1B genes in human primary open-angle glaucoma (POAG) has clearly been demonstrated, the mechanisms by which LMX1B mutations induce IOP elevation and glaucoma are not known. This project investigates the molecular mechanism by which abnormalities in LMX1B impact IOP and contribute to glaucoma. It will generate a more sophisticated understanding of a human glaucoma gene, ultimately guiding new treatments. Additionally, it will provide well characterized LMX1B glaucoma models to the community. Current IOP-lowering drugs are not effective in many patients, and reduce IOP by no more than 25-30%. Surgery to provide new aqueous humor (AQH) outlets often fails due to scar formation. Therefore, new IOP-lowering therapies are a critical need. New pathways and candidate molecules must be identified to advance development of more potent and specific anti-glaucoma targets. The specific nature of an inherited LMX1B variant is suggested to contribute to differences in glaucoma subtype and disease severity between individuals. We hypothesize that various LMX1B mutations have differential mechanistic effects - affecting LMX1B function or the function of other proteins that interact with LMX1B to regulate transcriptional activity/specificity. Our preliminary data support this hypothesis. We will test our hypothesis in the following aims: Aim 1) Determine the impact of selected Lmx1b mutations on phenotype and protein stability/function. Aim 2): Determine the molecular mechanism by which Lmx1b mutations impact IOP. Aim 3) Determine if Lmx1b impacts cellular metabolism and test a resilience boosting treatment.

高眼压（IOP）是青光眼的主要危险因素，也是所有治疗的目标目前的青光眼疗法。尽管 LMX1B 基因在人类初级中的重要性开角型青光眼（POAG）已被清楚地证明，其机制 LMX1B 突变导致眼压升高和青光眼尚不清楚。本项目调查 LMX1B 异常影响 IOP 并导致眼压升高的分子机制青光眼。它将对人类青光眼基因产生更复杂的理解，最终指导新的治疗方法。此外，它将提供特性良好的 LMX1B 向社区提供青光眼模型。目前的降眼压药物对许多疾病无效患者眼压降低不超过 25-30%。手术提供新的房水 (AQH) 出口经常因疤痕形成而失效。因此，新的降眼压疗法是关键需求。必须确定新的途径和候选分子才能取得进展开发更有效和特异性的抗青光眼靶标。的具体性质遗传性 LMX1B 变异被认为导致青光眼亚型和青光眼亚型的差异个体之间疾病的严重程度。我们假设各种 LMX1B 突变具有差异机制效应 - 影响 LMX1B 功能或其他蛋白质的功能与 LMX1B 相互作用以调节转录活性/特异性。我们的初步数据支持这个假设。我们将按照以下目标检验我们的假设：目标 1) 确定影响选定的 Lmx1b 突变对表型和蛋白质稳定性/功能的影响。目标 2)：确定 Lmx1b 突变影响 IOP 的分子机制。目标 3) 确定是否 Lmx1b 影响细胞新陈代谢并测试恢复力增强治疗。