SYSTEMIC VEGF AND DIABETIC RETINOPATHY--CLINICAL TRIALS

糖尿病视网膜病变导致的视力丧失主要发生在 新血管异常生长(增殖性)的并发症 糖尿病视网膜病变(PDR)或视网膜血管渗漏增加 (糖尿病黄斑水肿，DME)。我们之前已经证明了血管 血管内皮细胞生长因子(VEGF)是其中的主要介体。 并发症和血管内皮细胞生长因子的作用是通过激活 PKC-Beta。血管内皮生长因子和蛋白激酶C-β的抑制剂正在进入临床试验 用于治疗PDR和DME。血管内皮生长因子和PKC-Beta也都 与早期糖尿病视网膜病变的进展有关。 到目前为止，对患者的血管内皮生长因子的评估一直是有限的，因为 需要获取眼内液体样本或敏感度不足 血液化验。PI已经开发出高度敏感的VEGF Eliza 它可以很容易地检测到低基础水平的血管内皮生长因子在血液和 尿液。初步数据显示，外周血管内皮生长因子浓度可能 反映视网膜病变状态，受各种生理因素的影响 流程。血液或血清中的血管内皮生长因子是否与视网膜病变相关 那么从这些外周液体中测量出的血管内皮生长因子水平可能是 有助于识别有发生PDR或DME风险的患者，并 可能有助于监测抗血管内皮生长因子治疗的反应。此外, 我们已经合作开发了专门测量 激活人单核细胞中的PKC-β。 因此，具体的目标是：1)确定 外周血管内皮生长因子、眼血管内皮生长因子与糖尿病视网膜病变的交叉研究 横断面临床研究；2)确定 单核细胞中活化的PKC-β与糖尿病视网膜病变 3)确定血管内皮细胞生长因子在血管内皮生长因子中的作用。 糖尿病视网膜病变的前瞻性临床研究进展和 4)评价目前可用于血管内皮生长因子检测的新的血管内皮生长因子抗体。这个 一项横断面研究将评估200名1型糖尿病患者 也没有蛋白尿。视网膜病变程度将从以下方面评估 立体眼底照片。这些研究将提供第一个 严格检测血、尿血管内皮生长因子、活化的PKC-β和 糖尿病视网膜病变。这项前瞻性研究将评估血管内皮生长因子在 欧几里德研究中患者的血浆样本是一项 血管紧张素转换酶抑制剂的持续随机、安慰剂对照试验 赖诺普利在530名血压正常的队列患者中的应用 有正常或微量白蛋白尿，并随访两年。视网膜病变 水平和进展已被记录在案。这些研究将提供 首次前瞻性评价血浆血管内皮细胞生长因子及其与 视网膜病变进展和微量白蛋白尿的发病。

Visual loss from diabetic retinopathy occurs primarily from complications of either abnormal new vessel growth (proliferative diabetic retinopathy, PDR) or increased retinal vascular leakage (diabetic macular edema, DME). We have previously shown that vascular endothelial growth factor (VEGF) is a major mediator of these complications and that VEGF effects are mediated through activation of PKC-Beta. Inhibitors of VEGF and PKC-Beta are entering clinical trials for the treatment of PDR and DME. Both VEGF and PKC-Beta have also been implicated in the progression of early stages of diabetic retinopathy. To date, assessment of VEGF in patients has been limited due to either the need to obtain intraocular fluid samples or inadequate sensitivity of blood assays. The PI has developed a highly sensitive VEGF ELIZA which can readily detect the low basal levels of VEGF in both blood and urine. Preliminary data suggest that peripheral VEGF concentration may reflect retinopathy status and are effected by various physiologic processes. If VEGF in the blood or serum correlate with retinopathy level then measurement of VEGF from these peripheral fluids might be useful in identifying patients at risk of developing PDR or DME and might help in monitoring responses to anti-VEGF therapies. In addition, we have collaboratively developed techniques to specifically measure activated PKC-Beta in human monocytes. Thus, the specific aims: 1) Determine the correlation between peripheral VEGF, ocular VEGF and diabetic retinopathy in a cross- sectional clinical study; 2) Determine the correlation between activated PKC-Beta in monocytes and diabetic retinopathy in a cross- sectional clinical study; 3) Determine the role of VEGF in the progression of diabetic retinopathy in a prospective clinical study and 4) Evaluate novel VEGF antibodies now available for the VEGF assay. The cross-sectional studies will evaluate 200 patients with type 1 diabetes and no proteinuria. Retinopathy level will be assessed from stereoscopic fundus photographs. These studies will provide the first rigorous evaluation of serum and urine VEGF, activated PKC-Beta and diabetic retinopathy. The prospective study will evaluate VEGF in plasma samples obtained from patients in the EUCLID study which is a continuing randomized, placebo-controlled trial of the ACE inhibitor lisinopril in a well characterized cohort of 530 normotensive patients with normo- or microalbuminuria and two years follow-up. Retinopathy level and progression have been documented. These studies will provide the first prospective evaluation of plasma VEGF and its correlation with retinopathy progression and onset of microalbuminuria.