Sunday, November 24, 2024
11/24/2024
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.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
