Protective Factors Against the Development of Microvascular Complications

描述（由申请人提供）：确定糖尿病并发症机制的研究集中在高血糖症的毒性作用上。关于内源性保护因子可以预防或中和高血糖症的影响的研究很少。我们已经描述了一个大的胰岛素依赖50年或更长时间的患者队列（Medalists）。临床特征显示，87%和35%的奖牌获得者没有肾病和视网膜病变。血红蛋白（Hg）Ale水平、持续时间、胰岛素剂量和残余胰岛素产生与并发症状态无关。在初步研究中，两种类型的晚期糖基化终末产物与并发症减少相关，两种与水平增加相关。其他生化标志物，蛋白激酶6和酪氨酸磷酸酶（SHP-1），与缺乏增生性糖尿病视网膜病变（PDR）的高HgA 1c。此外，一项对奖章获得者的初步随访研究确定了一组受试者免受PDR的影响。基于支持内源性保护因子存在的试点数据，我们提出了三个协同项目，以确定他们在这个独特的队列。这些项目是：1）使用纵向、横断面和对照组研究扩展、表征和验证奖牌获得者队列的发现。增加的样本量（n=1000）将提供将传统和新型因素与通过蛋白质组学（项目1）、遗传学（项目2）和诱导多能干细胞（iPSC）生物学研究（项目3）确定的并发症状态进行统计学关联的把握度。 2)遗传部分将包括全基因组关联研究、外显子组测序，并与项目1合作，评估所确定的异常的细胞后果。项目1和项目2的结果将在年龄匹配的无糖尿病对照组、有和无并发症的1型糖尿病患者的年轻组以及英国既存的较小糖尿病患者队列中得到证实，这些患者的病程与我们的奖章获得者相似。3)本项目的目的是从Medalists和对照组（项目1）中获得IPSC并将其分化为成纤维细胞、内皮细胞、肾系膜细胞和周细胞。这些细胞将暴露于项目1和2中确定的高血糖条件和因素，以确定受保护的并发症与对照组与未受保护的奖牌获得者之间的差异。获奖者的独特资格以及来自细胞生物学、遗传学和成人干细胞生物学领先小组的综合专业知识，为确定1型和2型糖尿病患者血管并发症治疗设计中至关重要的保护因素带来了非凡的协同作用。 相关性：Medalist研究的目的是在一组1型糖尿病患者中确定可以保护糖尿病患者免受眼睛和肾脏疾病发展的因素，这些患者患有糖尿病超过50年，没有严重的任何眼睛，肾脏或神经并发症。

DESCRIPTION (provided by applicant): Studies to identify mechanisms for diabetic complications have focused on the toxic effects of hyperglycemia. There has been little work regarding endogenous protective factors that may prevent or neutralize the effects of hyperglycemia. We have characterized a large cohort of patients (Medalists) who have been insulin dependent for 50 or more years. Clinical characterization shows 87% and 35% of Medalists are free of nephropathy and retinopathy. Hemoglobin (Hg) Ale levels, duration, insulin dose, and residual insulin production did not correlate with complication status. In preliminary studies, two types of advanced glycation end products correlated with decreased complications and two with increased levels. Additional biochemical markers, protein kinase 6 and tyrosine phosphatase (SHP-1), correlated with a lack of proliferative diabetic retinopathy (PDR) in those with high HgA1c. Additionally, a pilot follow-up study of Medalists identified a group of subjects protected from PDR. Based on pilot data supporting the presence of endogenous protective factors; we propose three synergistic projects to identify them in this unique cohort. These projects are: 1) Expand, characterize and validate the findings of the Medalist cohort using both longitudinal, cross-sectional and control group studies. The increased sample size (n=1000) will provide the power to statistically relate traditional and novel factors with complication status identified through proteomic (project 1), genetic (project 2), and induced pluripotent stem cell (iPSC) biological studies (project 3). 2) The genetic component will include whole-genome association studies, exomic sequencing, and in collaboration with project 1 the evaluation of the cellular consequences of the abnormalities identified. Findings from projects 1 and 2 will be confirmed in an age-matched control group without diabetes, a younger group of type 1 diabetic patients with and without complications and a pre-existing smaller cohort of diabetic patients in the United Kingdom with similar disease duration as our Medalists. 3) The purpose of this project is to derive and differentiate IPSC from the Medalists and controls (project 1) into fibroblasts, endothelial cells, renal mesangial cells and pericytes. These cells will be exposed to hyperglycemic conditions and factors identified in projects 1 and 2 to determine the differences between who are protected from complications v controls v Medalists those not. The unique qualifies of the Medalists and the combined expertise from leading groups in cell biology, genetics and adult stem cell biology bring extraordinary synergy for identifying protective factors critical in designing therapies for vascular complications in type 1 and 2 diabetic patients. RELEVANCE: The aim of the Medalist Study is to identify factors that can protect diabetic patients from the development of eye and kidney disease in a group of type 1 diabetic patients who have survived with diabetes for more than 50 years without serious development of any eye, kidney or nerve complications.