Cellular Dysfunction in Exfoliation Glaucoma

剥脱性青光眼的细胞功能障碍

基本信息

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
项目类别：
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&apos 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

项目摘要

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：剥脱性青光眼剥脱综合征中的细胞功能障碍 (XFS) 是一种与年龄相关的疾病，涉及聚集纤维材料 (XFM) 的沉积细胞外基质。它的主要发病部位是眼睛，XFM 形成于眼睛表面。眼前节组织。 XFM 导致剥脱性青光眼 (XFG)，这是一种快速进展的疾病与全球约 1/3 的开角型青光眼 (POAG) 病例相关。鑫丰集团与许多与年龄相关的疾病相似，表现出明显的年龄依赖性作为聚集病。 LOXL1，一种基质交联酶，催化交联原弹性蛋白用于合成弹性纤维，是 XFM 的主要成分，已与 XFG 相关联然而，通过基因组学广泛协会研究，目前还不清楚 LOXL1 蛋白如何有助于疾病病理学。对 XFS/G 细胞基础的理解取得了进展由于缺乏实验模型而减慢了速度。使用原代人腱成纤维细胞 (TF) 源自 XFG 患者和对照（年龄匹配的 POAG 患者和 No- 青光眼患者），我们最近发现，XFG-TF 显示出许多功能特征在其他与年龄相关的聚集病（如帕金森病、阿尔茨海默病和 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 与 XFG 的开发联系起来，我们发现 XFG-TF a) 显示通过旨在中和错误折叠的机制增加了 LOXL1 输出新生多肽； b) 通过自噬处理 LOXL1，表明存在该蛋白质的错误折叠或变性单位； c) 积累细胞内蛋白质聚集体更高的内源表达； d) 在聚集响应性伴侣中过度表达簇- 像蛋白质。最后，LOXL1二级结构的计算机检查表明LOXL1 蛋白质的 N 末端具有基本结构，预计可提高聚集倾向。此外，LOXL1 完整蛋白或缺失蛋白的实验表明 LOXL1 确实具有高聚集倾向，并且这种倾向的位点位于在 N 末端的特定范围内。因此，我们寻求回答基本问题关于 XFG 病理学基础因素的问题。我们建议，SpA1) 研究分子导致微管功能缺陷的机制； SpA2) 研究细胞应激反应，以及 LOXL1 输出和错误折叠蛋白质机制与 SpA3 之间的联系）鉴定 LOXL1 序列的最小氨基酸序列和结构特征调节其聚集倾向。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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：
发表时间：
2020-08-06
期刊：
影响因子：
2
作者：
Selver, Ozlem Barut;Gurdal, Mehmet;Yagci, Ayse;Egrilmez, Sait;Palamar, Melis;Cavusoglu, Turker;Veral, Ali;Guven, Cagri;Ates, Utku;Wang, Zheng;Wolosin, J Mario
通讯作者：
Wolosin, J Mario

USP10 Targeted Self-Deliverable siRNA to Prevent Scarring in the Cornea.

USP10 靶向自传递 siRNA 可预防角膜疤痕。

DOI：
发表时间：
2020-09-04
期刊：
影响因子：
0
作者：
Boumil, Edward F;Castro, Nileyma;Phillips, Andrew T;Chatterton, Jon E;McCauley, Sean M;Wolfson, Alexey D;Shmushkovich, Taisia;Ridilla, Marc;Bernstein, Audrey M
通讯作者：
Bernstein, Audrey M

Exfoliation Syndrome: A Disease of Autophagy and LOXL1 Proteopathy.

剥脱综合征：一种自噬和 LOXL1 蛋白病的疾病。