A Novel Pathogenic Pathway for Diabetic Keratopathy

糖尿病是一个重大的公共卫生问题，也是最常见的慢性病之一 全世界。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的显著危险因素 糖尿病患者的视力下降。糖尿病角膜病变的特征是角膜上皮病变，减少 上皮厚度、氧化应激、炎症、角膜神经密度降低和角膜退化 敏感度。糖尿病角膜病变的发病机制尚不完全清楚，这是一种 重大的知识鸿沟。过氧化物酶体增殖物激活受体α(PPARα)是一种配体激活的转录因子 是脂肪代谢的关键调节因子。独立报道的两项大型前瞻性临床研究 PPARα激动剂非诺贝特对糖尿病视网膜病变有较强的治疗作用。然而， PPARα在糖尿病角膜病变中的意义仍有待研究。我们在过去助学金期间的研究 已经证明：1)糖尿病人供体角膜中PPARα水平降低 糖尿病动物模型。2)非诺贝特减轻大鼠角膜神经退行性变和角膜敏感度下降 糖尿病。3)单纯PPARα消融可导致角膜神经变性。4)糖尿病患者的原代基质细胞 人类捐赠者的神经营养分泌减少。5)PPARαKO减少神经营养物质的产生 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 发现非诺贝特预防糖尿病模型中的角膜线粒体功能障碍，而PPARαKO 减少角膜中线粒体的功能和含量。这个项目将解决一个假设，即 PPARα对糖尿病角膜病变和神经变性的保护作用 角膜细胞代谢功能障碍的正常化及神经营养微环境的改善 眼角膜。我们将研究激活或过度表达PPARα是否会缓解角膜病变和代谢 糖尿病角膜缺乏，而角膜PPARα消融术将加剧角膜神经变性 以及糖尿病患者的角膜病变。我们还将研究角膜的分子机制。 上皮/间质-神经相互作用，使用已建立的3D体外和体内模型。我们还将确定是否 PPARα通过上调细胞外小泡(EVS)中的神经营养因子促进神经支配。在小学 人类上皮细胞和基质细胞，我们将确定PPARα是否可以预防由 糖尿病的压力源。我们还将研究PPARα在调节自噬/有丝分裂吞噬中的作用和 角膜上皮/基质中的cGAS信号转导。拟议的研究将确定一种新的功能 PPARα在调节角膜代谢和糖尿病角膜病变发病机制中的作用。这个 这里要解决的假设挑战了糖尿病角膜病变的流行范式，以及研究结果 这一项目将有可能重新制定未来的治疗模式。因此，该项目具有较高的 翻译潜力，并可能导致一种新的治疗策略的糖尿病角膜病变。

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.