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Epac1 as a novel therapeutic target for diabetic retinopathy

Epac1作为糖尿病视网膜病变的新型治疗靶点

基本信息

批准号：
10689112
负责人：
XIAODONG CHENG
金额：
$ 50.62万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10689112
关键词：
Adult American Angiogenesis Inhibitors Apoptosis Applied Genetics Attenuated Biology Blindness Blood Vessels Blood capillaries Calcineurin Centers for Disease Control and Prevention (U.S.)Chronic Clinical Collaborations Complications of Diabetes Mellitus Cyclic AMP Development Diabetes Mellitus Diabetic Retinopathy Disease Dropout Dynamin E-Box Elements Elements Endothelial Cells Endothelium Etiology Eye diseases Face Functional disorder Genetic Glucose Hyperglycemia Hypoxia Hypoxia-Responsive Elements Intervention KDR gene Knockout Mice Laboratories Lead Mediating Medical Mitochondria Molecular Mus Notch Signaling Pathway Oxygen Pathogenesis Pathogenicity Pathologic Neovascularization Pericytes Pharmaceutical Preparations Play Prevention Production Prophylactic treatment Proteins Reactive Oxygen Species Reperfusion Therapy Retina Retinal Diseases Role Second Messenger Systems Signal Transduction Site Stress Response Signaling Symptoms Testing Therapeutic Vascular Diseases Vascular Endothelial Growth Factors Vascular remodeling aged aging population angiogenesis bevacizumab biological adaptation to stress calmodulin-dependent protein kinase II diabetic improved in vivo in vivo evaluation inhibitor innovation insight intravitreal injection mouse model neovascularization new therapeutic target notch protein novel novel therapeutic intervention novel therapeutics pharmacologic prevent promoter retinal damage retinal ischemia secretase standard care therapeutic target therapeutically effective trafficking

项目摘要

Each year, millions of Americans face vision loss related to diabetes. According to the U.S. Centers for Disease Control and Prevention, more than 30 million Americans have diabetes, and a third of diabetics aged 40 or over in the U.S. have diabetic retinopathy (DR) and related diabetic eye diseases. While the pathogenic mechanisms underpinning the development of DR appear multifactorial and remain incompletely understood, abnormal neovascularization is a key contributing factor, supported by the fact that therapy with anti-VEGF (vascular endothelial growth factor) drugs has become the gold standard treatment for DR and its complications among other interventions. Whilst anti-VEGFs demonstrate modest clinical benefits, these drugs fail to fully attenuate clinical progression or reverse damage to the retina and have to be administered frequently via invasive intravitreal injections over many years. Thus, there is a pressing need to develop new therapeutic strategies to improve the treatment of this devastating disease. A better understanding of the etiology and the molecular mechanism of DR, as well as the development of novel mechanism-based therapeutics, will address a major unmet medical need. This study combines genetic and pharmacological approaches to determine the functions and mechanisms of Epac1-mediated pathogenic neovascularization and vascular dysfunction during DR development. Successful completion of our proposed studies will not only provide new mechanistic insights into understanding cAMP/Epac1-mediated vascular remodeling but also will lead to the discovery of a new class of in vivo pharmacological agents that can be used as lead compounds for developing medications targeting DR and other vascular proliferative diseases.

每年，数百万美国人面临与糖尿病有关的视力丧失。据美国疾病中心称控制和预防，超过3000万美国人患有糖尿病，三分之一的糖尿病患者年龄在40岁或糖尿病视网膜病变（DR）和相关的糖尿病眼病。而致病的支持DR发展的机制似乎是多因素的并且仍然不完全清楚，异常新生血管形成是一个关键因素，抗VEGF治疗的事实支持了这一点血管内皮生长因子（vascular endothelial growth factor，VEGF）药物已成为DR及其并发症治疗的金标准。其他干预措施中的并发症。虽然抗VEGF显示出适度的临床益处，但这些药物不能完全减弱临床进展或逆转对视网膜的损伤多年来经常通过侵入性玻璃体内注射。因此，迫切需要开发新的治疗策略，以改善这种毁灭性疾病的治疗。更好地理解 DR的病因学和分子机制，以及基于新机制的治疗，将解决一个主要的未满足的医疗需求。这项研究结合了遗传学和药理学确定Epac 1介导的致病性新血管形成的功能和机制的方法， DR发展过程中的血管功能障碍。成功完成我们建议的研究，为理解cAMP/Epac 1介导的血管重塑提供了新的机制见解，导致发现了一类新的体内药理学试剂，其可用作先导化合物，开发针对DR和其他血管增生性疾病的药物。