Validation of Potential Protective Factors from Diabetic Complications

描述（由申请人提供）：确定糖尿病视网膜病变（DR）和糖尿病肾病（DN）的保护因素可以提供重要的生物标志物和治疗药物，以防止和阻止这两种毒性并发症显著降低生活质量。我们使用了一组独特的1型糖尿病（T1DM）患者，他们患病超过50年（奖牌获得者），我们已经开始通过死前和死后研究来确定DR和DN的潜在保护因素。我们通过临床检查、混合膳食耐受性试验、广泛的眼科检查和病史问卷调查，对600多名奖牌获得者进行了广泛的特征分析。令人惊讶的是，35%的患者没有或只有轻度DR (ETDRS <53)，不到14%的患者患有DN （ACR <70 mcg/mg）。死后组织学检查证实了这些发现。到目前为止，已经捐赠了超过16名奖牌获得者研究参与者的尸体标本。视网膜、玻璃体和肾小球标本的蛋白质组学图谱已经确定了DR和DN的第一组潜在保护因素。这是通过比较受影响组织和未受影响组织之间的蛋白质表达来完成的。根据通路作图和文献回顾，在肾小球分析中发现的14种候选蛋白都参与了燃料代谢。在视网膜分析中确定的10个因素涉及膜循环、运输、光导恢复和视网膜功能。生物信息学途径分析表明，DR候选基因与DN候选基因不重叠；然而，这两组保护因素表明，与患有相应疾病的运动员相比，没有DR或DN的运动员存在更活跃和代谢活跃的组织。本研究建议在奖牌获得者和另一组异常的超快速进展的糖尿病患者的血浆和循环细胞中测量所有确定和验证的候选物质。此外，将在DR和DN的培养视网膜血管和肾小球和小管细胞模型中研究抗高血糖暴露的能力。我们还将能够在细胞培养模型和糖尿病动物体内模型中确定这些潜在保护因子的生物学作用。从这些转化研究中，我们将能够识别和确认与DR和DN相关的潜在保护因素。

DESCRIPTION (provided by applicant): The identification of protective factors for Diabetic Retinopathy (DR) and Diabetic Nephropathy (DN) could provide important biomarkers and therapeutic agents to prevent and halt these two toxic complications from significantly diminishing quality of life. Using a unique population of type 1 diabetic (T1DM) patients with more than 50 years of disease (Medalists), we have begun to identify potential protective factors for DR and DN through pre and post mortem studies. We have extensively characterized over 600 Medalists through clinical examination, mixed meal tolerance test, extensive ophthalmic examination, and medical history questionnaires. Surprisingly, 35% have no or only mild DR (ETDRS <53), and less than 14% have DN (ACR <70 mcg/mg). Post-mortem histologic examinations confirm these findings. Thus far, post-mortem specimens from over 16 Medalist Study participants have been donated. Proteomic mapping of the specimens from the retina, vitreous, and renal glomeruli have identified a first set of potential protective factors for DR and DN. This was done by comparing protein expression between affected and unaffected tissues. According to pathway mapping and literature review, the fourteen candidate proteins identified in the glomerular analysis are all involved in fuel metabolism. The 10 factors identified in the retina analysis are involved in membrane recycling, transport, recovery of phototransduction, and retinal function. Bioinformatic pathway analyses demonstrate that the candidates identified for DR do not overlap with those for DN; however, both sets of protective factors suggest that more vibrant and metabolically active tissues exist in Medalists without DR or DN compared to those with the respective conditions. This study proposes to measure all of the identified and validated candidates in the plasma and circulating cells in the Medalists and in another unusual group of diabetic patients with ultra-fast progression. Additionally, the ability to protect against hyperglycemic exposure will be studied in cultured retinal vascular and renal glomerular and tubular cell models of DR and DN. We will also be able to determine the biological actions of these potential protective factors both in cell culture models and in vivo animal models of diabetes. From these translational studies, we will be able to identify and confirm potential protective factors associated with DR and DN.