Models, mechanisms and treatment of LMX1B-induced glaucoma

LMX1B诱发青光眼的模型、机制和治疗

• 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
• 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

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.

高眼压是青光眼的主要致病危险因素，也是所有青光眼的目标。 目前青光眼的治疗方法。尽管Lmx1b基因在人类原发疾病中的重要性 开角型青光眼(POAG)已被明确证实，其发病机制 Lmx1b基因突变导致眼压升高，青光眼尚不清楚。这个项目调查了 Lmx1b基因异常影响眼压并导致眼压升高的分子机制 青光眼。它将产生对人类青光眼基因的更复杂的理解， 最终指导新的治疗方法。此外，它还将提供具有良好特性的Lmx1b 把青光眼模特带到社区。目前的降眼压药物在许多情况下并不有效 患者，眼压下降不超过25%-30%。手术提供新的房水 (AQH)插座经常因疤痕形成而失效。因此，新的降眼压疗法是一种 迫切需要。必须确定新的途径和候选分子才能推进 开发更有效和更特异的抗青光眼靶点。一种特定性质的 遗传的Lmx1b变异被认为是青光眼亚型和 个体之间的疾病严重程度。我们假设不同的Lmx1b突变 不同的机制效应-影响Lmx1b的功能或其他蛋白质的功能 与Lmx1b相互作用，调节转录活性/特异性。我们的初步数据支持 这个假说。我们将在以下目标中检验我们的假设：目标1)确定影响 选择Lmx1b突变对表型和蛋白质稳定性/功能的影响。目标2)：确定 Lmx1b突变影响眼压的分子机制目标3)确定Lmx1b 影响细胞新陈代谢并测试增强复原力的治疗方法。