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

OGF-OGFr 轴调节可预防糖尿病眼表并发症。

基本信息

批准号：
10203997
负责人：
IAN S ZAGON
金额：
$ 37.05万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10203997
关键词：
Accounting Adult Affect American Animals Appearance Attention Basic Science Blindness Cardiovascular Diseases Cell Cycle Progression Cell Proliferation Chemicals Clinic Clinical Clinical Sciences Complications of Diabetes Mellitus Cornea Corneal Abrasion Corneal Diseases Cyclins Defect Development Diabetes Mellitus Disease Endorphins Enkephalins Epithelial Etiology Eye Abnormalities Female Financial Hardship Functional disorder Health Care Costs Hyperglycemia Individual Insulin Insulin-Dependent Diabetes Mellitus Intervention Keratopathy Knowledge Laboratories Lead MT3 gene Medical Methionine Enkephalin Mus Naltrexone Nuclear Receptors Occupations Opioid Antagonist Opioid Peptide Opioid Receptor Oryctolagus cuniculus Pathogenesis Pathway interactions Peptides Phosphotransferases Population Prediabetes syndrome Prevention approach Prevention therapy Preventive therapy Production Productivity Quality of life Rattus Regimen Regulatory Pathway Research Retinal Diseases Role Scientist Streptozocin Surface System Testing Time Topical application Translating United States base corneal epithelial wound healing diabetic diabetic rat disability endogenous opioids experience eye dryness male methionine-enkephalin receptor molecular marker ocular surface overexpression precision medicine prevent preventive intervention prophylactic protein biomarkers receptor receptor expression repaired

项目摘要

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.

项目摘要糖尿病在全球增加，超过9％的美国人口患有糖尿病，另外8600万糖尿病前的成年美国人。 1型糖尿病（T1D）影响了近150万美国人每年将近180亿美元的医疗保健费用。与糖尿病有关的并发症，例如视网膜病变和心血管疾病受到广泛关注，三种角膜疾病，包括角膜病，干眼症，表面不敏感会导致视力丧失，医疗保健成本提高以及提高工作生产力。这应用侧重于阿片类药物生长因子（OGF） - 阿片类药物生长因子受体（OGFR）调节纳曲酮（NTX）的系统和阻断，以防止1型糖尿病产生的眼表面并发症（T1D）。与糖尿病相关并发症的预防性干预仍然是未满足的医疗需求。基础该提议中的假设是糖尿病发育过程中OGF-OGFR轴失调导致过度表达抑制性肽和/或OGFR失调，从而导致糖尿病 - 相关的眼表并发症。拟议的研究将i）确定临时课程和在大鼠T1D发育过程中，OGF-OGFR调节途径中缺陷的大小，以便为了适当启动预防疗法，2）确定局部或全身施用NTX是否阻止或延迟眼表并发症的外观。 3）识别其他分子和蛋白质生物标志物与糖尿病有关，例如延迟角膜伤口愈合，干眼和不敏感，并确定是否是否 NTX干预改变了它们的表达和功能。这些知识将推进精度医学预防和治疗糖尿病并发症的方法。此应用程序代表数十年的研究的高潮确定NTX与NTX的OGF-OGFR阻滞有效治疗糖尿病性眼表面并发症，这是第一次确定这种封锁的能力 NTX预防糖尿病眼表面并发症。有证据表明糖尿病是通过内源性阿片类药物表达（即OGF）表达的失调及其接收器导致升高抑制生长因子的表达。超过20年，我们的实验室一直进行研究确定该调节轴在糖尿病大鼠，小鼠和兔子并证明局部NTX会逆转干眼至正常的泪水产生，加速延迟角膜伤口愈合，并恢复角膜敏感性降低正常的糖尿病并发症糖尿病动物。拟议的研究将首次确定OGF-OGFR轴封锁的能力由NTX防止这些并发症。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在这项研究中，将能够将有保证的发现迅速转化为诊所。