A Novel Pathogenic Pathway for Diabetic Keratopathy

糖尿病（Diabetes Mellitus，DM）是一种严重的公共卫生问题，也是最常见的慢性病之一 国际吧糖尿病眼部并发症、糖尿病视网膜病变和糖尿病角膜病变是糖尿病视网膜病变的显著危险因素。 糖尿病患者视力下降。糖尿病性角膜病变的特征是上皮病变， 上皮厚度、氧化应激、炎症、角膜神经密度降低和角膜厚度下降 敏感性糖尿病性角膜病变的发病机制尚不完全清楚，这代表了一种 重大知识缺口。过氧化物酶体激活受体-α（PeroxisomeCatalystator-ActivatedReceptor-α，PPARα）是一种配体激活的转录因子， 因子和脂质代谢的关键调节因子。两项大型前瞻性临床研究独立报告 PPARα激动剂非诺贝特对糖尿病视网膜病变具有强大的治疗作用。但 过氧化物酶体增殖物激活受体α在糖尿病性角膜病变中意义尚待进一步研究。我们在过去资助期内的研究 已经证明：1）糖尿病供体角膜和正常人角膜中的PPARα水平降低， 糖尿病动物模型。2)非诺贝特预防老年性角膜炎角膜神经变性和角膜敏感性下降 糖尿病3)单独的PPARα消融诱导角膜神经变性。4)糖尿病原代基质细胞 人类供体显示神经营养分泌减少。5)PPARα KO减少神经营养因子的产生 角膜中的因素。为了研究这些PPARα功能的分子基础，我们的初步研究 发现非诺贝特可预防糖尿病模型中角膜线粒体功能障碍，而PPARα KO 降低角膜中的线粒体功能和内容物。这个项目将解决一个假设， PPARα对糖尿病诱导的角膜病变和神经变性的保护作用是通过 角膜细胞代谢功能障碍的正常化和改善角膜中的神经营养微环境 角膜我们将研究是否激活或过度表达的过氧化物酶体增殖物激活受体α将减轻角膜病变和代谢 糖尿病角膜中的PPAR α缺乏，而角膜中的PPARα消融将加剧角膜神经变性 和糖尿病中的角膜病变。我们还将研究角膜炎的分子机制， 上皮/基质-神经相互作用，使用建立的3D体外和体内模型。我们还将确定， PPARα通过上调细胞外囊泡（EV）中的神经营养因子促进神经支配。小学 人上皮细胞和基质细胞，我们将确定PPARα是否可以防止由 糖尿病应激源我们还将研究PPARα在自噬/线粒体自噬调节中的作用， 角膜上皮/基质中的cGAS-STING信号传导。拟议的研究将确定一种新的功能， 过氧化物酶体增殖物激活受体α对角膜代谢的调节及糖尿病角膜病变的新机制的 这里要解决的假设挑战了糖尿病性角膜病变的流行模式， 将有可能重新构建未来的治疗模式。因此，该项目具有很高的 翻译潜力，并可能导致糖尿病角膜病变的新的治疗策略。

Diabetes Mellitus (DM) is a major public health problem and one of the most prevalent chronic diseases worldwide. DM ocular complications, diabetic retinopathy and diabetic keratopathy, are eminent risk factors for visual deterioration in DM patients. Diabetic keratopathy is characterized by epithelial lesion, reduction of epithelium thickness, oxidative stress, inflammation, decreased corneal nerve densities and declined corneal sensitivities. The pathogenic mechanism for diabetic keratopathy is not fully understood, which represents a major knowledge gap. Peroxisome Proliferator-Activated Receptor-α (PPARα) is a ligand-activated transcription factor and a key regulator of lipid metabolism. Two large and prospective clinical studies reported independently that the PPARα agonist fenofibrate has robust therapeutic effects on diabetic retinopathy. However, the implication of PPARα in diabetic keratopathy remains to be investigated. Our studies in the past grant period have demonstrated that: 1) PPARα levels are decreased in the corneas of diabetic human donors and of a diabetic animal model. 2) Fenofibrate alleviates corneal nerve degeneration and decline of corneal sensitivity in diabetes. 3) PPARα ablation alone induces corneal nerve degeneration. 4) Primary stromal cells from diabetic human donors showed decreased neurotrophic secretion. 5) PPARα KO reduces production of neurotrophic factors in the cornea. To investigate the molecular basis for these PPARα functions, our preliminary studies found that fenofibrate prevents corneal mitochondrial dysfunction in a diabetic model, while PPARα KO decreases mitochondrial function and contents in the cornea. This project will address a hypothesis that the protective effect of PPARα against diabetes-induced corneal keratopathy and nerve degeneration is through normalization of metabolic dysfunction in corneal cells and improving the neurotrophic microenvironment in the cornea. We will investigate if activation or overexpression of PPARα will alleviate keratopathy and metabolic deficiency in the diabetic cornea, while PPARα ablation in the cornea will exacerbate corneal nerve degeneration and keratopathy in diabetes. We will also investigate the molecular mechanisms for the corneal epithelium/stroma-nerve interactions, using established 3D in vitro and in vivo models. We will also determine if PPARα promotes innervation via upregulation of neurotrophic factors in extracellular vesicles (EVs). In primary human epithelial and stromal cells, we will determine if PPARα prevents metabolic deficiencies induced by diabetic stressors. We will also investigate the role of PPARα in the modulation of autophagy/mitophagy and cGAS-STING signaling in the corneal epithelium/stroma. The proposed studies will identify a novel function of PPARα in the regulation corneal metabolism and a new pathogenic mechanism for diabetic keratopathy. The hypotheses to be addressed here challenges the prevailing paradigm of diabetic keratopathy, and the findings from this project will have the potential to reframe the future treatment modalities. Thus, this project has high translational potential and may lead to a new therapeutic strategy for diabetic keratopathy.