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。 糖尿病前期的美国成年人1型糖尿病（T1 D）影响近150万美国人，占20%。 每年的医疗费用将近180亿美元。糖尿病相关并发症，如视网膜病变和 心血管疾病受到公众的广泛关注，3种角膜疾病包括角膜病，干眼， 和表面不敏感性导致视力丧失、医疗保健成本升高和工作效率降低。这 阿片样生长因子受体（OGFr）的调节作用 纳洛酮（NTX）预防1型糖尿病引起的眼表并发症 （T1D）。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。底层 在这个提议中的一个假设是OGF-OGFr轴在糖尿病的发展过程中变得失调 导致抑制肽的过度表达和/或OGFr的失调，从而引起糖尿病- 相关的眼表并发症。拟议的研究将i）确定时间进程， 在大鼠T1 D发展过程中，OGF-OGFr调节通路的缺陷程度， 适当地开始预防性治疗，2）确定局部或全身施用NTX是否预防或 延缓眼表并发症的出现。3)识别其他分子和蛋白质生物标志物 与糖尿病相关的，如角膜伤口愈合延迟、干眼和不敏感，并确定是否 NTX干预改变了它们的表达和功能。这些知识将推动精准医疗 预防和治疗糖尿病并发症的方法。此应用程序代表了 几十年的研究结果表明，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着 内源性阿片样物质表达的失调（即，OGF）及其受体导致 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， 确定该调节轴在糖尿病大鼠、小鼠和小鼠中促成糖尿病并发症的作用， 兔并证明局部NTX可逆转干眼症至正常泪液产生，加速延迟泪液产生 角膜伤口愈合，并恢复糖尿病并发症的角膜敏感性下降，在这些 糖尿病动物这项研究将首次确定OGF-OGFr轴阻断的能力。 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专业知识 这项研究，并将能够迅速翻译保证的结果，以临床。

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.