Protective Factors Against the Development of Microvascular Complications

防止微血管并发症发生的保护因素

• 批准号: 8150968
• 负责人: GEORGE L KING
• 金额: $ 80.16万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8150968
• 关键词: Acceleration; Advanced Glycosylation End Products; Affect; Age; Animal Model; Apoptosis; Biochemical Markers; Biochemistry; Biological; Biological Assay; Blindness; Blood Vessels; Cardiovascular Pathology; Cells; Cellular biology; Chronic; Chronic Kidney Failure; Clinical; Cohort Studies; Collaborations; Complication; Complications of Diabetes Mellitus; Control Groups; Country; DBA/2 Mouse; Data; Development; Diabetes Mellitus; Diabetic Angiopathies; Diabetic Nephropathy; Disease; Dose; Endogenous Factors; Endothelial Cells; Evaluation; Exhibits; Eye; Eye diseases; Fibroblasts; Functional RNA; Funding; Genes; Genetic; Glucose; Growth Factor; Hemoglobin; Hyperglycemia; In Vitro; Insulin; Insulin-Dependent Diabetes Mellitus; Kidney; Kidney Diseases; Kidney Glomerulus; Longitudinal Studies; Modeling; Monoclonal Antibody R24; Morbidity - disease rate; Nerve; Open Reading Frames; Oxidative Stress; PTPN6 gene; Participant; Pathology; Pathway interactions; Patients; Pattern; Pericytes; Phosphotransferases; Plasma; Platelet-Derived Growth Factor; Principal Investigator; Production; Protein Kinase; Protein Tyrosine Phosphatase; Proteins; Proteomics; Qualifying; Recruitment Activity; Reporting; Research Methodology; Residual state; Retina; Retinal; Retinal Diseases; Sample Size; Serum; Technology; Time; Toxic effect; Translating; United Kingdom; United States National Institutes of Health; Urine; Validation; Vascular Endothelial Growth Factors; Visit; Work; adult stem cell; base; clinical phenotype; cohort; diabetic; diabetic patient; effective therapy; follow-up; genetic variant; genome wide association study; illness length; induced pluripotent stem cell; mesangial cell; monocyte; mortality; novel; podocyte; prevent; proliferative diabetic retinopathy; stem cell biology; success; therapy design; type I diabetic

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.

描述（由申请人提供）：确定糖尿病并发症机制的研究重点关注高血糖的毒性作用。关于可预防或中和高血糖影响的内源性保护因子的研究很少。我们对一大批已经依赖胰岛素​​ 50 年或更长时间的患者（奖章获得者）进行了特征分析。临床特征显示，87% 和 35% 的奖牌获得者没有肾病和视网膜病。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，另两种则与水平增加相关。其他生化标志物蛋白激酶 6 和酪氨酸磷酸酶 (SHP-1) 与 HgA1c 高的患者缺乏增殖性糖尿病视网膜病变 (PDR) 相关。此外，一项针对奖牌获得者的试点后续研究确定了一组免受 PDR 保护的受试者。基于支持内源性保护因素存在的试点数据；我们提出了三个协同项目来在这个独特的群体中识别出他们。这些项目是： 1) 使用纵向、横断面和对照组研究来扩展、描述和验证奖章获得者队列的研究结果。增加的样本量（n = 1000）将提供将传统和新因素与通过蛋白质组学（项目1）、遗传（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关联的能力。 ）。 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 合作评估所识别异常的细胞后果。项目 1 和 2 的结果将在年龄匹配的无糖尿病对照组、年轻的有或没有并发症的 1 型糖尿病患者组以及英国预先存在的较小组糖尿病患者中得到证实，这些患者的病程与我们的奖牌获得者。 3) 该项目的目的是将奖牌获得者和对照组（项目 1）的 IPSC 衍生并分化为成纤维细胞、内皮细胞、肾系膜细胞和周细胞。这些细胞将暴露于项目 1 和项目 2 中确定的高血糖条件和因素中，以确定免受并发症的患者与对照组与未获得并发症的奖牌获得者之间的差异。奖牌获得者的独特资质以及细胞生物学、遗传学和成体干细胞生物学领域领先团队的综合专业知识，为识别 1 型和 2 型糖尿病患者血管并发症的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：奖章获得者研究的目的是在一组 1 型糖尿病患者中找出可以保护糖尿病患者免受眼部和肾脏疾病发展的因素，这些患者在糖尿病中存活了 50 多年，但任何眼睛都没有严重发育，肾脏或神经并发症。