Role of betacellulin in diabetic macular edema

描述(申请人提供)：糖尿病在世界范围内的发病率，预计到2025年将达到流行比例。糖尿病视网膜病变的进展往往导致糖尿病黄斑水肿，这是血-视网膜屏障破坏，视网膜血管通透性增加，血浆从黄斑小血管渗漏导致中心视力丧失的结果。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，虽然强化糖尿病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相关(Ismail-Beigi，2010年6月29日，《柳叶刀》在线)，以及低血糖发作的更高发病率风险。我们的理由是，关键是确定一个下游的血糖目标，它导致视网膜血管通透性增加，可以作为治疗靶点，而不会增加与强化治疗高血糖相关的风险。β细胞蛋白是表皮生长因子家族中一个32kD的成员，由胰岛细胞增殖产生，促进胰腺细胞再生。根据我们的初步研究，我们假设β-细胞蛋白在糖尿病相关的视网膜血管并发症中发挥了作用，这些研究表明，糖尿病小鼠视网膜血管通透性增加，伴随而来的是裂解形式的可溶性β-细胞蛋白(S-BTC)在视网膜中的表达增加。在正常血糖和高血糖小鼠中，玻璃体内注射Betacellin导致视网膜出血和血管通透性增加。在糖尿病小鼠和患有糖尿病视网膜病变的人的视网膜中，去整合素和金属蛋白酶ADAM-10(在β细胞蛋白的裂解中起作用)增加。基于这些初步结果，我们假设β-细胞蛋白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。

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.