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Lens capsule and secondary cataract

晶状体囊和继发性白内障

基本信息

批准号：
10706997
负责人：
Ram H Nagaraj
金额：
$ 36.39万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
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/10706997
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 Cell secretion Cells Complication Country Data Development Disease Economic Burden Elderly Epithelial Cells Epithelial Receptor Cell 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 Link Mediating Mesenchymal Methods Modification Molecular Pathogenesis Patients Performance Phenotype Post-Translational Protein Processing Production Proliferating Proteins Quality of life Reaction Reactive Oxygen Species Receptor Down-Regulation Research Resistance Retinal Detachment Role Testing Tissues Transforming Growth Factors Vision Visual Visual impairment aged amino group antagonist 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 lens induction migration novel novel therapeutics paracrine prevent protein structure receptor downregulation receptor for advanced glycation endproducts response retinal damage senescence sight restoration therapy development time interval transdifferentiation

项目摘要

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.

项目总结