Cellular Dysfunction in Exfoliation Glaucoma

剥脱性青光眼的细胞功能障碍

• 批准号: 9980044
• 负责人: AUDREY M BERNSTEIN
• 金额: $ 42.68万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9980044
• 关键词: Affect; Age; Age related macular degeneration; Aging; Alzheimer' s Disease; Amino Acid Sequence; Amino Acids; Anterior; Autophagocytosis; Cell Line; Cells; Cellular Stress Response; Cellular biology; Chimera organism; Chronic; Ciliary Body; Code; Complex; Coupled; Dangerousness; Data; Deacetylase; Defect; Dependence; Deposition; Development; Disease; Elastic Fiber; Endoplasmic Reticulum Degradation Pathway; Enzymes; Ethnic Origin; Exfoliation Syndrome; Experimental Models; Extracellular Matrix; Extracellular Protein; Eye; Fibroblasts; Functional disorder; Generations; Genetic; Genomics; Glaucoma; HDAC6 gene; Health; Health Status; Human; Huntington Disease; Impairment; Iris; Link; Liquid substance; Mediating; Microtubules; Mitochondria; Molecular; Molecular Chaperones; Morbidity - disease rate; Neurodegenerative Disorders; Open-Angle Glaucoma; Parkinson Disease; Pathology; Pathway interactions; Patients; Population; Positioning Attribute; Primary Open Angle Glaucoma; Process; Protein Export Pathway; Protein-Lysine 6-Oxidase; Proteins; Publishing; Quality Control; Risk; Role; Skin; Source; Stretching; Structure; Surface; System; Testing; Tissues; Trabecular meshwork structure; Trabeculectomy; Tropoelastin; Ubiquitin; Variant; age related; cell immortalization; crosslink; experimental study; high risk; improved; in silico; lens; misfolded protein; multicatalytic endopeptidase complex; overexpression; polypeptide; preservation; protein aggregation; proteostasis; response; sulfated glycoprotein 2

Project Summary/Abstract: Cellular Dysfunction in Exfoliation Glaucoma Exfoliation syndrome (XFS) is an age-related disease involving the deposition of aggregated fibrillar material (XFM) in extracellular matrices. Its main morbidity is in the eye, where XFM forms on the surface of anterior segment tissues. XFM causes exfoliation glaucoma (XFG), a rapidly progressing disease associated with approximately 1/3 of open-angle glaucoma (POAG) cases worldwide. XFG demonstrates a sharp age-dependence in similarity to the many age-related diseases qualified as aggregopathies. LOXL1, a matrix cross-linking enzyme that catalyzes the crosslinking of tropoelastin for the synthesis of elastic fibers and a major component of XFM, has been linked to XFG by Genomics Wide Association Studies, however, it is still unclear how LOXL1 protein contributes to disease pathology.Progress in understanding the cellular basis for XFS/G has been slowed by a lack of experimental models. Working with primary human tenon fibroblasts (TF) derived from trabeculectomies of XFG patients and controls (age-matched POAG patients and No- Glaucoma patients), we recently found that, XFG-TFs display many of the functional features observed in cells from other age-related aggregopathies such as Parkinson's, Alzheimer's, and AMD including defects in lysosomal positioning, autophagy, microtubule organization and function, and mitochondrial health status. Linking LOXL1 to the development of XFG, we have found that XFG-TF a) display increased LOXL1 export by a mechanism aimed at neutralizing misfolded nascent polypeptides; b) process LOXL1 through autophagy indicating the presence of misfolded or denatured units of this protein; c) accumulate intracellular protein aggregates with higher endogenous expression; and d) overexpress clusterin an aggregate-responsive chaperone- like protein. Finally, an in silico examination of LOXL1 secondary structure indicated that LOXL1 protein has elemental structures within the N-terminus that are predicted to confer an increased aggregation propensity. Furthermore, experiments of LOXL1 whole protein or with deletions shows that indeed LOXL1 has high aggregation propensity and that the loci of this propensity reside within specific stretches of the N-terminus. Accordingly, we seek to answer fundamental questions on the factors that underpin XFG pathology. We propose, SpA1) to study the molecular machinery leading to the defects in microtubule function; SpA2) to investigate cellular stress responses, and the connection between LOXL1 export and misfolded protein machinery, and SpA3) to identify the minimal amino acid sequences and structural features of the LOXL1 sequence that mediate its aggregation propensity.

项目摘要/摘要：脱落性青光眼脱落综合征的细胞功能障碍