Molecular Dysregulation in Fuchs Corneal Endothelial Dystrophy

摘要 Fuchs角膜内皮营养不良症（FECD）是一种致盲性疾病，影响数百万人（4%以上）。 40岁）在美国，这是没有治愈。内皮细胞丢失，细胞外基质增厚 (ECM)或后弹力膜，在患有以下疾病的患者中观察到细胞外沉积物（滴状物）的存在： FECD。角膜移植是目前流行的治疗方法，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，内皮细胞表达增加， 间充质转化（EMT）基因，并且未折叠蛋白的积累存在于FECD中。在 根据目前的建议，我计划确定和描述a）未折叠蛋白质积累的原因 和细胞中的其它碎片，和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）， FECD细胞显著减少。在目标1和目标2中，我计划确定氧化应激是否是 这些降低的活性，使用药理学试剂来恢复自噬和UPP的功能， 确定这些是否可以缓解疾病进展。整合素活性增加和Wnt降低 在FECD中观察到信号传导。已知这两种信号通路都调节EMT，这意味着 FECD疾病进展。在目标3中，我计划确定氧化应激是否是上调的原因 在FECD中整合素和Wnt通路的抑制，并评估这些信号转导对 急救员我计划在印第安纳州大学布卢明顿的K99阶段进行目标1和2。除了 我将从目前的实验室中独立出来，我也将参加职业发展机会 印第安纳州大学布卢明顿提供的，以准备就业市场，提高科学交流， 以及指导技能。目标3将在R 00阶段进行。圆满完成这些目标 将导致FECD中错误的分子机制的识别和表征， 确定这些途径的恢复是否足以改善疾病进展。

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.