Validation of Potential Protective Factors from Diabetic Complications

验证糖尿病并发症的潜在保护因素

基本信息

批准号：
8922182
负责人：
GEORGE L KING
金额：
$ 13.05万
依托单位：
JOSLIN DIABETES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-30 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8922182
关键词：
Action Potentials Affect Animal Model Bioinformatics Biological Biological Assay Biological Markers Blood Vessels Cell Culture Techniques Cell model Cells Clinical Clinical Trials Complications of Diabetes Mellitus Cultured Cells Data Diabetes Mellitus Diabetic Angiopathies Diabetic Nephropathy Diabetic Retinopathy Disease Epidemiologic Studies Functional disorder Future Glucose Histologic Human Human Pathology Hyperglycemia Individual Insulin-Dependent Diabetes Mellitus Kidney Kidney Diseases Kidney Glomerulus Liquid substance Maps Measures Medical History Membrane Metabolic Metabolism Microvascular Dysfunction Participant Pathology Pathway interactions Patients Phototransduction Plasma Population Proteins Proteomics Quality of life Questionnaires Recovery Recycling Retina Retinal Retinal Diseases Review Literature Rodent Model Sampling Severities Specimen Staging Testing Therapeutic Therapeutic Agents Time Tissues Toxic effect Transgenic Mice Tubular formation Validation aqueous base bevacizumab diabetic diabetic patient effective therapy experience human tissue illness length in vivo Model kidney vascular structure prevent protein expression theories translational study type I diabetic

项目摘要

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.

描述（由申请人提供）：糖尿病视网膜病（DR）和糖尿病肾病（DN）保护因素的鉴定可以提供重要的生物标志物和治疗药物，以预防和阻止这两种毒性并发症显着降低生活质量。利用病龄超过 50 年的 1 型糖尿病 (T1DM) 患者（奖章获得者）这一独特人群，我们已开始通过尸检前和尸检研究来确定 DR 和 DN 的潜在保护因素。我们通过临床检查、混合膳食耐受性测试、广泛的眼科检查和病史调查问卷，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% 的人没有或仅有轻度 DR (ETDRS <53)，不到 14% 的人有 DN (ACR <70 mcg/mg)。尸检组织学检查证实了这些发现。到目前为止，超过 16 名奖章获得者研究参与者的尸检标本已被捐赠。对视网膜、玻璃体和肾小球样本的蛋白质组图谱确定了第一组 DR 和 DN 的潜在保护因素。这是通过比较受影响和未受影响的组织之间的蛋白质表达来完成的。根据通路图谱和文献综述，肾小球分析中确定的 14 种候选蛋白均参与燃料代谢。视网膜分析中确定的 10 个因素涉及膜回收、运输、光转导恢复和视网膜功能。生物信息学通路分析表明，针对 DR 确定的候选药物与针对 DN 的候选药物并不重叠；然而，两组保护因素表明，与患有相应病症的获奖者相比，没有 DR 或 DN 的奖章获得者存在更有活力和代谢活跃的组织。这项研究计划测量获奖者和另一组进展超快的不寻常糖尿病患者的血浆和循环细胞中所有已识别和验证的候选者。此外，还将在培养的 DR 和 DN 视网膜血管、肾小球和肾小管细胞模型中研究预防高血糖暴露的能力。我们还将能够确定这些潜在保护因子在细胞培养模型和糖尿病体内动物模型中的生物学作用。从这些转化研究中，我们将能够识别并确认与 DR 和 DN 相关的潜在保护因素。