SYSTEMIC VEGF AND DIABETIC RETINOPATHY--CLINICAL TRIALS

糖尿病视网膜病变的视力丧失主要发生在 异常的新血管生长（增殖性）或 糖尿病视网膜病变，PDR）或视网膜血管渗漏增加 （糖尿病性黄斑水肿，DME）。 我们之前已经证明， 内皮生长因子（VEGF）是这些的主要介质。 并发症和VEGF的作用是通过激活 PKC-β VEGF和PKC-β抑制剂正在进入临床试验 治疗PDR和DME。 VEGF和PKC-β也被 与糖尿病视网膜病变的早期进展有关。 迄今为止，由于以下原因，对患者VEGF的评估有限： 需要获得眼内液样本或灵敏度不足 血液化验。 PI已开发出高度敏感的VEGF ELISA 其可以容易地检测血液中VEGF的低基础水平， 尿 初步数据表明，外周血管内皮生长因子浓度可能 反映视网膜病变的状态，并受各种生理 流程. 如果血液或血清中的VEGF与视网膜病变相关 水平，然后测量这些外周液中的VEGF可能是 可用于识别有发生PDR或DME风险的患者， 可能有助于监测抗VEGF治疗的反应。 此外，本发明还提供了一种方法， 我们合作开发了专门测量的技术 激活人单核细胞中的PKC β。 因此，具体目标是：1）确定 外周血管内皮生长因子，眼血管内皮生长因子和糖尿病视网膜病变的交叉研究 部分临床研究; 2）确定 单核细胞中激活的PKC-β与糖尿病视网膜病变的交叉研究 部分临床研究; 3）确定VEGF在 在一项前瞻性临床研究中， 4)评价目前可用于VEGF检测的新型VEGF抗体。的 横断面研究将评估200例1型糖尿病患者 也没有蛋白尿 视网膜病变水平将从 立体眼底照片。 这些研究将首次提供 严格评估血清和尿液VEGF、活化PKC-β和 糖尿病视网膜病变。 这项前瞻性研究将评估VEGF在 从欧几里得研究中的患者获得的血浆样本， ACE抑制剂的连续随机、安慰剂对照试验 赖诺普利在530例血压正常患者中的特征性队列研究 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。 这些研究将提供 首次前瞻性评价血浆VEGF及其与 视网膜病变进展和微量白蛋白尿的发生。

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.