Lens capsule and secondary cataract

晶状体囊和继发性白内障

• 批准号: 10433474
• 负责人: Ram H Nagaraj
• 金额: $ 37.89万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10433474
• 关键词: Adherence; Adult; Advanced Glycosylation End Products; Age; Aging; Amino Acids; Anterior; Apoptosis; Aqueous Humor; Binding; Biochemical; Biochemical Pathway; CRISPR/Cas technology; Cataract; Cataract Extraction; Cell Aging; Cell physiology; Cells; Complication; Country; Data; Development; Disease; Down-Regulation; Economic Burden; Elderly; Epithelial Cells; Extracellular Matrix; Eye; Fibrosis; Future; Goals; Growth; Growth Factor; Health Care Costs; Human; Impairment; In Situ; Inflammatory; Innovative Therapy; Interleukin-6; Intraocular lens implant device; Lasers; Lead; Link; Mediating; Mesenchymal; Methods; Modification; Molecular; Pathogenesis; Patients; Performance; Phenotype; Post-Translational Protein Processing; Production; Proliferating; Proteins; Quality of life; Reaction; Reactive Oxygen Species; Research; Resistance; Retinal Detachment; Role; Testing; Tissues; Transforming Growth Factors; Vision; Visual; Visual impairment; aged; amino group; antagonist; base; capsule; carbonyl compound; cell type; clinical predictors; crosslink; cytokine; epithelial to mesenchymal transition; epithelial wound; extracellular; fiber cell; glycation; in vivo; knock-down; lens; lens capsule; migration; novel; novel therapeutics; paracrine; prevent; protein structure; receptor for advanced glycation endproducts; response; retinal damage; senescence; sight restoration; therapy development; time interval; transdifferentiation

PROJECT SUMMARY Posterior capsular opacification (PCO) is a major vision-impairment problem that emerges after cataract surgery and Nd:YAG laser posterior capsulotomy is required to restore vision. During PCO, the lens epithelial cells (LECs) that remain tethered to the anterior capsule after cataract surgery proliferate, migrate to the posterior capsule where they undergo epithelial-to-mesenchymal transition (EMT) and secrete extracellular matrix, leading to fibrous tissue formation along with wrinkling of the posterior capsule. Transforming growth factor-2 (TGFβ2) has been proposed as a major driver of EMT. We have previously demonstrated that the advanced glycation end products (AGEs) present in aged lens capsules promote the TGFβ2-mediated EMT of LECs. In our preliminary studies for this proposal, we have discovered that capsule-AGEs through binding to RAGE receptor promote senescence of LECs. We have also observed that senescent LECs promote EMT of nonsenescent LECs through paracrine mechanisms. Our data also suggest a greater synthesis of TGFβ2 in senescent cells than nonsenscent cells. Based on these observations, we propose a novel hypothesis that capsule AGEs induce senescence in LECs, which promotes the EMT of LECs during posterior capsule opacification. This hypothesis is further supported by our recent observation of senescent cells in the posterior capsules of psuedophakic human donor eyes. In Aim 1, we will test the hypothesis that lens capsule AGEs induce senescence of LECs through formation of reactive oxygen species in cells cultured on AGE- modified extracellular matrix. In Aim 2, we will test the hypothesis that senescent cells promote the EMT of human LECs through paracrine mechanisms. The secretion of TGFβ2 and IL-6 from senescent cells and their ability to induce EMT in nonsenescent cells will be investigated. In Aim 3, we will test the hypothesis that inhibition/downregulation of RAGE prevents LEC senescence and PCO-like changes in human capsular bags. Together, the proposed studies are expected to expand our understanding of the molecular mechanisms of lens fibrosis and aid in the development of novel drugs for treating PCO.

项目概要 后囊膜混浊（PCO）是白内障后出现的主要视力障碍问题 在 PCO 期间，需要进行手术和 Nd:YAG 激光后囊切开术来恢复视力。 白内障手术后仍束缚在前囊上的细胞（LEC）增殖并迁移到 后囊膜，在那里它们经历上皮间质转化（EMT）并分泌细胞外 基质，导致纤维组织形成以及后囊起皱。 因子-2 (TGFβ2) 被认为是 EMT 的主要驱动因素。 老化晶状体囊中存在的晚期糖基化终末产物 (AGE) 促进 TGFβ2 介导的 EMT 在我们针对该提案的初步研究中，我们发现胶囊-AGE 通过结合到 RAGE受体促进LECs的衰老我们还观察到衰老的LECs促进EMT。 我们的数据还表明，非衰老 LEC 通过旁分泌机制合成了更多的 TGFβ2。 基于这些观察，我们提出了一个新的假设： 囊AGEs诱导LECs衰老，从而促进后囊膜期间LECs的EMT 我们最近对衰老细胞的观察进一步支持了这一假设。 在目标 1 中，我们将检验晶状体囊的假设。 AGE 通过在 AGE 上培养的细胞中形成活性氧来诱导 LEC 衰老 在目标 2 中，我们将检验衰老细胞促进 EMT 的假设。 人类 LEC 通过旁分泌机制从衰老细胞及其中分泌 TGFβ2 和 IL-6。 在目标 3 中，我们将研究在非衰老细胞中诱导 EMT 的能力。 抑制/下调 RAGE 可防止人囊袋中 LEC 衰老和 PCO 样变化。 总之，拟议的研究有望扩大我们对分子机制的理解 晶状体纤维化并有助于开发治疗 PCO 的新药物。