Molecular Dysregulation in Fuchs Corneal Endothelial Dystrophy

福克斯角膜内皮营养不良的分子失调

• 批准号: 10468155
• 负责人: Rajalekshmy Shyam
• 金额: $ 11.27万
• 依托单位: TRUSTEES OF INDIANA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10468155
• 关键词: Affect; Age; Agonist; American; Autophagocytosis; Bulla; Cell Death; Cell physiology; Cells; Characteristics; Communication; Cornea; Corneal Endothelium; Corneal edema; Cytoskeleton; Data; Deposition; Descemet' s membrane; Disease; Disease Progression; Endothelial Cells; Endothelium; Epithelial; Eukaryota; Eukaryotic Cell; Extracellular Matrix; Eye diseases; Focal Adhesion Kinase 1; Fuchs' Endothelial Dystrophy; Genes; Glycogen Synthase Kinases; Goals; Growth Factor; Indiana; Integrins; Keratoplasty; Lead; Mediating; Mentors; Mesenchymal; Molecular; Oxidative Stress; Pathway interactions; Patients; Peptides; Persons; Pharmacology; Phase; Phenotype; Phosphorylation; Population; Production; Proteins; Reactive Oxygen Species; Repression; Role; Sampling; Science; Signal Pathway; Signal Transduction; Specimen; Testing; Therapeutic; Transducers; Ubiquitin; Universities; Up-Regulation; WNT Signaling Pathway; antagonist; career development; endoplasmic reticulum stress; experimental study; extracellular; functional restoration; improved; job market; mitochondrial dysfunction; multicatalytic endopeptidase complex; protein expression; response; restoration; skills; ubiquitin-protein ligase

Abstract Fuchs Corneal Endothelial Dystrophy (FECD) is a blinding disease that affects millions of people (4% over the age of 40) in the U.S, for which there is no cure. Endothelial cell loss, thickening of the extra cellular matrix (ECM) or Descemet’s membrane, presence of extracellular deposits (guttae) are observed in patients with FECD. Corneal transplantation is the prevalent treatment approach, and FECD accounts for the majority of corneal transplantations in the world. On a cellular level, increased oxidative stress, expression of endothelial to mesenchymal transition (EMT) genes, and an accumulation of unfolded proteins are present in FECD. In the current proposal, I plan to identify and characterize the reasons for a) the accumulation of unfolded proteins and other debris in the cells, and b) elevated EMT. Our preliminary data show that the components of two main protein clearance pathways in eukaryotes; autophagy and the ubiquitin proteasome pathway (UPP), are significantly reduced in FECD cells. In Aims 1 and 2, I plan to identify whether oxidative stress is the cause for these decreased activities, use pharmacological agents to restore functions of autophagy and UPP, and determine whether these can alleviate the disease progression. Increased integrin activity and decreased Wnt signaling was observed in FECD. Both these signaling pathways are known to regulate EMT, which implicated in FECD disease progression. In Aim 3, I plan to determine if oxidative stress is the cause for the upregulation of integrin and repression of Wnt pathways in FECD, and to assess the roles of these signal transductions on EMT. I plan to conduct Aims 1 and 2 during the K99 phase in Indiana University Bloomington. In addition to establishing my independence from my current lab, I will also take part in career development opportunities available at Indiana University Bloomington to prepare for the job market, improve science communication as well as mentoring skills. Aim 3 will be performed during the R00 phase. Successful completion of these aims will lead to the identification and characterization of molecular mechanisms that are awry in FECD, and determine whether restoration of these pathways would suffice in the amelioration of the disease progression.

摘要 Fuchs角膜内皮营养不良症(FECD)是一种影响数百万人(4%以上)的致盲疾病 40岁)在美国，这是无法治愈的。内皮细胞丢失，细胞外基质增厚 (ECM)或Descemet膜，观察到细胞外沉积(牙胶)的存在 FECD。角膜移植是流行的治疗方法，而FECD占大多数 世界上最大的角膜移植手术。在细胞水平上，氧化应激增加，内皮细胞表达 间充质转化(EMT)基因和未折叠蛋白的积累存在于FECD中。在 目前的提议，我计划确定和表征a)未折叠蛋白质积累的原因 和细胞中的其他碎片，以及b)EMT升高。我们的初步数据显示，两个主要的成分 真核生物中的蛋白质清除途径；自噬和泛素蛋白酶体途径(UPP)，是 在FECD细胞中显著减少。在目标1和目标2中，我计划确定氧化应激是否是导致 这些活性降低，使用药物来恢复自噬和UPP的功能，以及 确定这些药物是否可以减缓疾病的进展。整合素活性增加，Wnt减少 在FECD中观察到信号传导。这两个信号通路都是已知的调节EMT的信号通路，这意味着 在FECD疾病进展中。在目标3中，我计划确定氧化应激是否是上调的原因 研究整合素和Wnt通路在FECD中的抑制作用，并评估这些信号转导在FECD中的作用 急诊室。我计划在印第安纳大学布鲁明顿分校的K99阶段进行目标1和目标2。除了……之外 从目前的实验室中独立出来，我还将参与职业发展机会 在印第安纳大学布鲁明顿分校提供，为就业市场做准备，改善科学交流 以及指导技能。目标3将在R00阶段执行。圆满完成这些目标 将导致鉴定和表征FECD中错误的分子机制，以及 确定这些通路的恢复是否足以改善疾病的进展。