Cellular Dysfunction in Exfoliation Glaucoma

剥脱性青光眼的细胞功能障碍

• 批准号: 10663210
• 负责人: AUDREY M BERNSTEIN
• 金额: $ 41.13万
• 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 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10663210
• 关键词: Acetylation; Affect; Age; Age related macular degeneration; Aging; Alzheimer' s Disease; Amino Acid Sequence; Amino Acids; Anterior; Autophagocytosis; Cell Aggregation; Cell Line; Cells; Cellular Stress; Cellular biology; Chimera organism; Chronic; Ciliary Body; Code; Coupled; Dangerousness; Data; Deacetylase; Defect; Dependence; Deposition; Development; Disease; Disease Progression; Elastic Fiber; Elements; 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; Qualifying; 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：剥离青光眼去角色综合征的细胞功能障碍 （XFS）是一种与年龄相关的疾病 细胞外矩阵。它的主要发病率在于眼睛，其中XFM在表面形成 前节组织。 XFM引起去角色青光眼（XFG），这是一种快速发展的疾病 与全球大约1/3的开态青光眼（POAG）病例相关。 XFG 表现出与许多与年龄有关的疾病的相似性急剧依赖性 作为聚集病。 LOXL1，一种基质交联酶，可催化交联的交联 用于合成弹性纤维和XFM的主要组成部分的Tropoelastin已与XFG链接 但是，通过基因组学广泛的关联研究，尚不清楚LOXL1蛋白如何 有助于疾病病理学。了解XFS/G的细胞基础的过程已经 由于缺乏实验模型而减慢。与原发性人体田纳成纤维细胞（TF）一起工作 源自XFG患者和对照组的小梁切除术（年龄匹配的POAG患者和NO- 青光眼患者），我们最近发现，XFG-TFS显示了许多功能特征 在其他与年龄相关的聚集病的细胞中观察到，例如帕金森氏症，阿尔茨海默氏症和 AMD包括溶酶体定位，自噬，微管组织和功能的缺陷， 和线粒体健康状况。将loxl1链接到XFG的开发，我们发现 XFG-TF A）显示通过一种旨在中和错误折叠的机制增加LOXL1的导出 新生多肽； b）通过自噬的过程loxl1，表明存在 该蛋白质的错误折叠或变性单位； c）与 较高的内源性表达； d）过表达簇蛋白骨料反应性伴侣 - 喜欢蛋白质。最后，在LOXL1二级结构的硅硅检查中表明LOXL1 蛋白质具有N末端内的元素结构，这些结构被预测赋予增加 聚集倾向。此外，LOXL1全蛋白或用缺失的实验显示 确实，Loxl1具有很高的聚集倾向，并且该倾向的基因座位于 在N末端的特定拉伸中。因此，我们试图回答基本 关于基于XFG病理的因素的问题。我们建议SPA1）研究分子 机械导致微管功能的缺陷； SPA2）研究细胞应激 响应，以及LOXL1导出与错误折叠的蛋白质机械和SPA3之间的连接） 确定LOXL1序列的最小氨基酸序列和结构特征 调解其聚合倾向。

项目成果

LOXL1 folding in exfoliation glaucoma.

• DOI: 10.1016/bs.apcsb.2019.09.005
• 发表时间: 2019
• 期刊: Advances in protein chemistry and structural biology
• 作者: Bernstein AM;Ritch R;Wolosin JM
• 通讯作者: Wolosin JM

Exfoliation Syndrome: A Disease of Autophagy and LOXL1 Proteopathy.

• DOI: 10.1097/ijg.0000000000000919
• 发表时间: 2018-07
• 期刊: Journal of glaucoma
• 影响因子: 2
• 作者: Bernstein AM;Ritch R;Wolosin JM
• 通讯作者: Wolosin JM

Multi-parametric evaluation of autologous cultivated Limbal epithelial cell transplantation outcomes of Limbal stem cell deficiency due to chemical burn.

化学烧伤导致角膜缘干细胞缺乏的自体培养角膜缘上皮细胞移植结果的多参数评估。

• DOI: 10.1186/s12886-020-01588-6
• 发表时间: 2020
• 期刊: BMC ophthalmology
• 影响因子: 2
• 作者: Selver,OzlemBarut;Gurdal,Mehmet;Yagci,Ayse;Egrilmez,Sait;Palamar,Melis;Cavusoglu,Turker;Veral,Ali;Guven,Cagri;Ates,Utku;Wang,Zheng;Wolosin,JMario
• 通讯作者: Wolosin,JMario