Lens capsule and secondary cataract

晶状体囊和继发性白内障

• 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
• 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

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 后囊混浊(PCO)是白内障后出现的主要视力障碍问题。 需要手术和后囊切开术以恢复视力。在PCO中，晶状体上皮细胞 白内障手术后仍拴在前囊上的细胞(LECs)增殖，迁移到 在后囊中，它们经历上皮向间充质转化(EMT)并分泌细胞外 基质，导致纤维组织形成和后囊皱折。转型增长 转化生长因子-2(Fel--2，β-2)已被认为是子宫内膜异位症的主要驱动力。我们之前已经证明了 老年晶状体囊内晚期糖基化终产物促进转化生长因子β-2介导的小鼠晶状体上皮细胞转化 LECs。在我们对这一提议的初步研究中，我们发现胶囊-通过结合到 RAGE受体促进晶状体上皮细胞衰老。我们还观察到衰老的晶状体上皮细胞促进EMT 非衰老的晶状体上皮细胞通过旁分泌机制。我们的数据也表明转化生长因子β-2在 衰老细胞多于无感觉细胞。基于这些观察，我们提出了一个新的假设 囊膜AGE诱导晶状体上皮细胞衰老，促进晶状体上皮细胞后囊膜EMT 混浊。这一假说进一步得到了我们最近对衰老细胞的观察。 人工晶状体眼的后囊。在目标1中，我们将检验晶状体胶囊的假设 AGEs通过在体外培养的晶状体上皮细胞中形成活性氧来诱导LECs衰老。 修饰的细胞外基质。在目标2中，我们将检验衰老细胞促进脑组织EMT的假说。 人晶状体上皮细胞通过旁分泌机制。衰老细胞分泌转化生长因子β-2和IL-6及其机制 在非衰老细胞中诱导EMT的能力将被研究。在目标3中，我们将检验假设 抑制/下调RAGE可防止人类囊袋中LEC衰老和PCO样改变。 总之，拟议的研究有望扩大我们对糖尿病的分子机制的理解。 晶状体纤维化和帮助开发治疗后囊混浊的新药。