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.

项目摘要 后囊膜混浊是白内障后出现的一个主要的视力障碍问题 需要手术和Nd：YAG激光后囊膜切开术来恢复视力。在PCO期间，透镜上皮 白内障手术后仍然束缚在前囊上的晶状体上皮细胞（LEC）增殖，迁移到晶状体前囊， 后囊，在那里它们经历上皮向间充质转化（EMT）并分泌细胞外 基质，导致纤维组织形成沿着后囊的扩张。转化生长 已提出TGFβ2是EMT的主要驱动因素。我们以前已经证明， 存在于老化透镜囊膜中的晚期糖基化终末产物（AGEs）促进TGFβ2介导的 LEC。在我们对这一建议的初步研究中，我们发现，胶囊AGEs通过结合到 β受体促进晶状体上皮细胞的衰老。我们还观察到衰老的LEC促进EMT， 非衰老LEC通过旁分泌机制。我们的数据还表明， 衰老细胞比无感细胞多。基于这些观察，我们提出了一个新的假设， 囊膜AGEs可诱导晶状体上皮细胞衰老，从而促进晶状体上皮细胞在后囊膜期的EMT 不透明化我们最近对衰老细胞的观察进一步支持了这一假设。 人工晶状体供体眼的后囊膜。在目标1中，我们将检验透镜囊 AGEs通过在AGE-1上培养的细胞中形成活性氧来诱导LEC衰老。 修饰的细胞外基质。在目的2中，我们将检验衰老细胞促进细胞的EMT的假设。 人类LEC通过旁分泌机制。衰老细胞分泌TGFβ_2和IL-6的变化及其意义 将研究在非衰老细胞中诱导EMT的能力。在目标3中，我们将检验以下假设： 在人囊袋中，抑制/下调LEC可防止LEC衰老和PCO样变化。 总之，拟议的研究有望扩大我们对以下分子机制的理解： 透镜纤维化，并有助于开发治疗PCO的新药。