Role of betacellulin in diabetic macular edema

描述（由申请人提供）：预计到2025年，全球糖尿病的发病率将达到流行病的比例。糖尿病性视网膜病变的进展通常导致糖尿病性黄斑水肿，这是血液-视网膜屏障破坏、视网膜血管通透性增加和血浆从黄斑中的小血管渗漏导致中心视力丧失的结果。高血糖的程度和糖尿病的持续时间已被证明是视网膜并发症的良好预测因子。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率增加的风险相关（Ismail-Beigi，2010年6月29日，Lancet在线）以及与低血糖发作的更高发病风险相关。我们的理由是，这是至关重要的，以确定一个下游血糖目标，导致视网膜血管通透性增加，可以有针对性的治疗，而没有额外的风险与高血糖症的强化治疗。β细胞素是表皮生长因子家族的32 kD成员，其通过增殖胰岛细胞产生并促进胰腺细胞的再生。基于我们的初步研究，我们假设β细胞素在与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具有加重的视网膜血管通透性，伴随着视网膜中裂解的可溶性形式的β细胞素（s-Btc）的表达增加。玻璃体内注射β-细胞素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。去整合素和金属蛋白酶ADAM-10（其在β细胞素的裂解中起作用）在糖尿病小鼠和患有糖尿病视网膜病变的人的视网膜中增加。基于这些初步结果，我们假设β细胞素有助于视网膜血管通透性增加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.