Role of betacellulin in diabetic macular edema

β细胞素在糖尿病黄斑水肿中的作用

• 批准号: 8449210
• 负责人: BELA ANAND-APTE
• 金额: $ 37.29万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8449210
• 关键词: Binding; Blindness; Blood Vessels; Blood-Retinal Barrier; Cardiovascular Diseases; Cells; Cleaved cell; Complications of Diabetes Mellitus; Development; Diabetes Mellitus; Diabetic Retinopathy; Diabetic mouse; Disintegrins; Epidemic; Epidemiologic Studies; Epidermal Growth Factor; Extravasation; Exudate; Family; Future; Human; Hyperglycemia; Hyperglycemic Mice; Hypoglycemia; Incidence; Insulin; Intervention Studies; Islet Cell; Lead; Liquid substance; Maintenance; Membrane; Metalloproteases; Modality; Molecular; Morbidity - disease rate; Natural regeneration; Non-Insulin-Dependent Diabetes Mellitus; Pancreas; Pathogenesis; Pathology; Patients; Permeability; Physiological; Plasma; Play; Proliferating; Reporting; Retina; Retinal; Retinal Diseases; Retinal Hemorrhage; Risk; Role; Smooth Muscle Myocytes; Structure of retinal pigment epithelium; Testing; Tight Junctions; Vascular Permeabilities; Vision; base; betacellulin; diabetic; disorder of macula of retina; glycemic control; high risk; intravitreal injection; macula; macular edema; member; mortality; prevent; proliferative diabetic retinopathy; public health relevance; retina blood vessel structure; solute; therapeutic development

DESCRIPTION (provided by applicant): The incidence of diabetes world-wide, is expected to reach epidemic proportions by 2025. Progression of diabetic retinopathy often results in diabetic macular edema, which is a consequence of the breakdown of the blood-retinal barrier, increased retinal vascular permeability and leakage of plasma from small blood vessels in the macula leading to loss of central vision. The degree of hyperglycemia and duration of diabetes have been shown to be good predictors of retinal complications. Intervention studies have determined that while intensive treatment of diabetes reduced the development of proliferative diabetic retinopathy it was associated with an increased risk of mortality from cardiovascular disease (Ismail-Beigi June 29, 2010 Lancet online) as well as with a higher morbidity risk from hypoglycemic episodes. We reason that it is critical to identify a downstream glycemic target that causes increased retinal vascular permeability that could be targeted therapeutically without the additional risks associated with intensive treatment of the hyperglycemia. Betacellulin is a 32 kD member of the epidermal growth factor family that is produced by proliferating ¿ cells of the islets and promotes regeneration of pancreatic ¿ cells. We hypothesize a role for betacellulin in the retinal vascular complications associated with diabetes based on our preliminary studies, which show that diabetic mice have accentuated retinal vascular permeability with a concomitant increased expression of a cleaved soluble form of betacellulin (s-Btc) in the retina. Intravitreal injection of betacellulin induced retinal hemorrhage and increased vascular permeability in normoglycemic and hyperglycemic mice. A disintegrin and metalloproteinase, ADAM-10 (which plays a role in the cleavage of betacellulin), is increased in the retinae of diabetic mice and humans with diabetic retinopathy. Based on these preliminary results we hypothesize that betacellulin contributes to increased retinal vascular permeability and the pathogenesis of diabetic macular edema.

描述（由申请人提供）：到2025年，全球糖尿病的发病率预计将达到流行病的程度。糖尿病视网膜病变的进展通常导致糖尿病性黄斑水肿，这是血视网膜屏障破裂、视网膜血管通透性增加和黄斑小血管血浆渗漏导致中央视力丧失的结果。高血糖程度和糖尿病病程已被证明是视网膜并发症的良好预测指标。干预研究已经确定，虽然糖尿病的强化治疗减少了增殖性糖尿病视网膜病变的发展，但它与心血管疾病死亡风险的增加有关（Ismail-Beigi， 2010年6月29日，柳叶刀在线），以及低血糖发作的发病率风险较高。我们认为，确定导致视网膜血管通透性增加的下游血糖靶标是至关重要的，这种靶标可以靶向治疗，而不会带来与高血糖强化治疗相关的额外风险。Betacellulin是一个32 kD的表皮生长因子家族成员，由胰岛增殖细胞产生并促进胰腺细胞再生。根据我们的初步研究，我们假设β -纤维素蛋白在糖尿病相关的视网膜血管并发症中的作用，这些研究表明，糖尿病小鼠视网膜血管通透性增强，同时视网膜中β -纤维素蛋白（s-Btc）的裂解可溶性形式表达增加。玻璃体内注射β -纤维素蛋白诱导正常血糖和高血糖小鼠视网膜出血和血管通透性增加。一种崩解素和金属蛋白酶ADAM-10（在β细胞蛋白的分裂中起作用）在糖尿病小鼠和糖尿病视网膜病变患者的视网膜中增加。基于这些初步结果，我们假设β细胞素有助于增加视网膜血管通透性和糖尿病黄斑水肿的发病机制。