Lens capsule and secondary cataract

晶状体囊和继发性白内障

基本信息

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
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/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

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

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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.

项目摘要后囊壳不透明（PCO）是白内障后出现的主要视力障碍问题手术和ND：YAG激光后囊切开术才能恢复视力。在PCO期间，镜片上皮白内障手术繁殖后仍滞留到前囊的细胞（LEC）迁移到后胶囊，它们经历上皮到间质转变（EMT）和秘密细胞外基质，导致纤维组织形成以及后囊的包裹。改变增长因素 - 2（TGFβ2）已被提出为EMT的主要驱动力。我们以前已经证明了具有老化晶状体胶囊中的晚期糖基化末端产品（年龄）促进了TGFβ2介导的EMT的EMT lecs。在我们针对该提案的初步研究中，我们发现胶囊时代通过结合到愤怒受体促进LEC的感应。我们还观察到，感觉LEC促进通过旁分泌机制非素质的LEC。我们的数据还表明TGFβ2在感官细胞比非浓缩细胞。基于这些观察，我们提出了一个新的假设，即胶囊年龄在LEC中诱导感应，该LEC促进了后囊期间LEC的EMT 卵子化。我们最近观察到的感觉细胞进一步支持伪造的人类供体眼后胶囊。在AIM 1中，我们将测试镜头胶囊的假设年龄通过在年龄培养的细胞中形成活性氧，诱导LEC的感受修饰的细胞外基质。在AIM 2中，我们将检验以下假设：感觉细胞促进EMT的EMT 人体通过旁分泌机制。 TGFβ2和IL-6从感觉细胞及其分泌 AIM 3，我们将检验以下假设愤怒的抑制/下调可防止人囊袋的LEC感应和PCO样变化。共同期望拟议的研究将扩大我们对分子机制的理解晶状体纤维化和有助于开发用于治疗PCO的新药物。