Role of Leukocyte-endothelial Adhesion in Diabetic Retinopathy

 描述（由申请人提供）：糖尿病诱导全身性低度慢性炎症反应。白细胞是全身炎症的关键介质。在糖尿病的背景下，白细胞聚集和粘附在视网膜微血管功能障碍的部位增加。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相关。本提案的目的是评估糖尿病患者之间白细胞内皮粘附的差异是否有助于糖尿病视网膜病变的结局。这项研究将确定白细胞内皮粘附是否是糖尿病视网膜病变的独立危险因素。虽然认识到白细胞介导的炎症在糖尿病视网膜病变的发病机制中起重要作用，但其相关性和临床重要性目前尚不清楚。本研究假设白细胞内皮粘附是糖尿病视网膜病变的一种新的生物标志物。具体而言，本提案将测试白细胞内皮粘附是否1）与糖尿病视网膜病变严重程度的不同阶段相关; 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）与其他微血管和大血管并发症（包括肾病、神经病变和心血管疾病）相关。研究目的将通过使用一项在具有良好特征的糖尿病视网膜病变人类受试者中进行的大型前瞻性临床研究来实现。因此，本研究将利用DCCT/EDIC队列的所有1，441例受试者的样本，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研究对受试者进行了为期25年的前瞻性随访。获得与来自数千名患有糖尿病视网膜病变的人类受试者的精细表征的前瞻性临床数据相关的疾病相关人体组织是非常宝贵的。将使用一种创新的高通量测定法来确定所有1，441名DCCT/EDIC研究受试者的白细胞内皮粘附的个体水平。总之，该提案将使用来自大型临床研究的人类样本来确定新的细胞特性白细胞内皮粘附是否与糖尿病视网膜病变结局相关。研究和治疗糖尿病视网膜病变的能力由于缺乏独特的、有效的和可翻译的疾病生物标志物而受到极大的阻碍。如果成功，这项研究的工作将建立一个新的生物标志物和糖尿病视网膜病变的独立危险因素的个人的白细胞内皮细胞粘附水平。这些发现可能对这种疾病的诊断、管理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.