OGF-OGFr Axis Modulation to Prevent Diabetic Ocular Surface Complications.

项目摘要 糖尿病在全球范围内不断增加，超过9%的美国人口患有糖尿病，另有8600万人患有糖尿病 糖尿病前期的成年美国人。1型糖尿病(T1D)影响近150万美国人，占 每年近180亿美元的医疗成本。糖尿病相关并发症，如视网膜病变和 心血管疾病备受关注，角膜病变、干眼、 而表面不敏感会导致视力丧失、医疗成本上升和工作效率下降。这 阿片生长因子-阿片生长因子受体调控的应用 纳曲酮(NTX)系统和阻断预防1型糖尿病眼表并发症 (T1D)。对糖尿病相关并发症的预防性干预仍然是一个未得到满足的医疗需求。潜在的 该方案的假设是OGF-OGFr轴在糖尿病的发展过程中变得失调。 导致抑制肽过度表达和/或OGFr调节失调，从而导致糖尿病- 相关的眼表并发症。拟议的研究将：i)确定时间进程和 在大鼠T1D发育过程中OGF-OGFr调控通路的缺陷程度 适当地启动预防性治疗，2)确定局部或全身应用NTX是否可以预防或 延缓眼表并发症的出现。3)确定其他分子和蛋白质生物标志物 与糖尿病有关，如角膜伤口愈合延迟、眼睛干燥和感觉迟钝，并确定是否 NTX干预改变了它们的表达和功能。这一知识将推动精确医学的发展 糖尿病并发症的防治方法。此应用程序表示 几十年的研究确定，用NTX阻断OGF-OGFr对 治疗糖尿病眼表并发症，并将首次确定这种阻断的能力 NTX预防糖尿病眼表并发症。有证据表明糖尿病伴随有 内源性阿片类药物(即OGF)及其受体表达失调导致血管活性升高 抑制生长因子的表达。二十多年来，我们的实验室一直在进行研究 确定此调节轴在糖尿病大鼠、小鼠和小鼠糖尿病并发症中的作用 并证明了局部使用NTX可以使干眼恢复正常的泪液分泌，加速延迟 角膜伤口愈合，并恢复糖尿病并发症，降低角膜对正常的敏感性 患糖尿病的动物。拟议的研究将首次确定OGF-OGFr轴的阻断能力 NTX来预防这些并发症。我们的研究团队在各个方面都有临床和基础科学的专业知识。 并将能够迅速将有保证的发现转化为临床。

Project Summary Diabetes is increasing globally and more than 9% of the US population has diabetes, with an additional 86 million pre-diabetic adult Americans. Type 1 diabetes mellitus (T1D) affects nearly 1.5 million Americans, accounting for almost $18 billion annually in healthcare costs. Diabetic-related complications such as retinopathy and cardiovascular disease receive much public attention, and 3 corneal disorders including keratopathy, dry eye, and surface insensitivity lead to vision loss, elevated healthcare costs, and decreased job productivity. This application focuses on the Opioid Growth Factor (OGF) – Opioid Growth Factor Receptor (OGFr) regulatory system and blockade by naltrexone (NTX) to prevent ocular surface complications arising from Type 1 diabetes (T1D). Preventive intervention of diabetes-related complications remains an unmet medical need. The underlying hypothesis in this proposal is that the OGF-OGFr axis becomes dysregulated during the development of diabetes leading to over-expression of the inhibitory peptide and/or dysregulation of OGFr thus causing diabetes- associated ocular surface complications. The proposed research will i) Determine the temporal course and magnitude of defects in the OGF-OGFr regulatory pathway during the development of T1D in rats in order to properly initiate preventive therapy, 2) Determine whether topical or systemic administration of NTX prevents or delays the appearance of ocular surface complications. 3) Identify other molecular and protein biomarkers related to diabetes such as delayed corneal wound healing, dry eye, and insensitivity, and determine whether NTX intervention alters their expression and function. This knowledge will advance precision medicine approaches for the prevention and treatment of diabetic complications. This application represents the culmination of several decades of research determining that OGF-OGFr blockade with NTX is effective at treating diabetic ocular surface complications, and for the first time, will determine the ability of such blockade by NTX to prevent diabetic ocular surface complications. There is evidence that diabetes is accompanied by dysregulation in expression of endogenous opioids (i.e., OGF) and their receptors leading to an elevated expression of inhibitory growth factors. For more than 2 decades our laboratory has conducted research to determine the role of this regulatory axis in contributing to diabetic complications in diabetic rat, mouse, and rabbit and demonstrated that topical NTX reverses dry eye to normal tear production, accelerates delayed corneal wound healing, and restores the diabetic complication of decreased corneal sensitivity to normal in these diabetic animals. The proposed research will determine for the first time the ability of OGF-OGFr axis blockade by NTX to prevent these complications. Our research team has clinical and basic science expertise in all aspects of this research and will be able to rapidly translate warranted findings to the clinic.