Role of Leukocyte-endothelial Adhesion in Diabetic Retinopathy

 描述(申请人提供)：糖尿病引起全身低度慢性炎症反应。白细胞是全身炎症的关键介质。在糖尿病的背景下，视网膜微血管功能障碍部位的白细胞聚集和黏附增加。糖尿病视网膜病变的恶化程度与白细胞内皮细胞粘附量的增加有关。这项建议的目的是评估糖尿病患者之间白细胞内皮细胞黏附的差异是否有助于糖尿病视网膜病变的预后。这项研究将确定白细胞内皮细胞黏附是否代表糖尿病视网膜病变的独立危险因素。虽然白细胞介导的炎症在糖尿病视网膜病变的发病机制中起着重要作用，但其相关性和临床重要性目前尚不清楚。本研究的假设是白细胞内皮细胞黏附是糖尿病视网膜病变的一个新的生物标志物。具体地说，这项建议将测试白细胞内皮细胞黏附1)与糖尿病视网膜病变严重程度的不同阶段有关；2)受强化血糖控制、累积血糖、糖尿病病程或其他因素的影响；3)预测糖尿病视网膜病变的进展；或4)与其他微观和宏观血管并发症有关，包括肾病、神经病变和心血管疾病。研究目标将通过对糖尿病视网膜病变的特征良好的人类受试者进行大型前瞻性临床研究来实现。因此，这项研究将利用DCCT/EDIC队列中所有1441名受试者的样本，这是一项具有里程碑意义的糖尿病视网膜病变临床研究。DCCT/EDIC研究前瞻性地跟踪了受试者超过25年的时间。获取与疾病相关的人体组织与数千名患有糖尿病视网膜病变的人类受试者的精致特征相关的前瞻性临床数据是非常宝贵的。一种创新的高通量测试将用于确定所有1,441名DCCT/EDIC研究对象的白细胞内皮细胞黏附的个体水平。总而言之，这项建议将使用来自大型临床研究的人类样本来确定一种新的细胞特性--白细胞内皮细胞黏附--是否与糖尿病视网膜病变的预后相关。由于缺乏唯一的、有效的和可翻译的糖尿病视网膜病变生物标志物，研究和治疗糖尿病视网膜病变的能力受到了相当大的阻碍。如果成功，这项研究的工作将确定一个人的白细胞内皮细胞黏附水平是一种新的生物标记物和糖尿病视网膜病变的独立危险因素。这些发现可能会对这种疾病的诊断、治疗和治疗产生直接的临床影响。

 DESCRIPTION (provided by applicant): Diabetes induces a systemic low-grade chronic inflammatory response. Leukocytes are a key mediator of inflammation throughout the body. In the setting of diabetes leukocyte aggregation and adhesion are increased at sites of retinal microvascular dysfunction. Worsening degrees of diabetic retinopathy correlate with increasing amounts of leukocyte endothelial adhesion. The objective of this proposal is to assess whether differences in leukocyte endothelial adhesion between individuals with diabetes contribute to diabetic retinopathy outcomes. The study will determine whether leukocyte endothelial adhesion represents an independent risk factor for diabetic retinopathy. While it is recognized that leukocyte mediated inflammation plays an important role in the pathogenesis of diabetic retinopathy, its relevance and clinical importance are presently unknown. The hypothesis of this study is that leukocyte endothelial adhesion represents a novel biomarker for diabetic retinopathy. Specifically, this proposal will test whether leukocyte endothelial adhesion 1) Is associated with different stages of diabetic retinopathy severity; 2) Is affected by intensive glycemic control, cumulative glycemia, diabetes duration or other factors; 3) Predicts the progression of diabetic retinopathy; or 4) Is associated with other micro and macro vascular complications including nephropathy, neuropathy and cardiovascular disease. The study objectives will be accomplished through the use of a large prospective clinical study of well-characterized human subjects with diabetic retinopathy. Accordingly, this study will leverage samples from all 1,441 subjects of the DCCT/EDIC cohort, a landmark clinical study of diabetic retinopathy. The DCCT/EDIC study prospectively followed subjects over a twenty-five year period. Access to disease relevant human tissue associated with exquisitely characterized prospective clinical data from thousands of human subjects with diabetic retinopathy is invaluable. An innovative high-throughput assay will be used to determine individual levels of leukocyte endothelial adhesion for all 1,441 DCCT/EDIC study subjects. In summary, this proposal will use human samples from a large clinical study to determine whether a novel cellular property, leukocyte endothelial adhesion, correlates with diabetic retinopathy outcomes. The ability to study and treat diabetic retinopathy has been hampered considerably by lack of a unique, valid and translatable biomarker for the disease. If successful, work from this study would establish an individual's level of leukocyte endothelial adhesion as a novel biomarker and independent risk factor for diabetic retinopathy. Such findings could have immediate clinical implications that bear on the diagnosis, management, and treatment of this condition.