Validation of Potential Protective Factors from Diabetic Complications

验证糖尿病并发症的潜在保护因素

• 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
• 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

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）：糖尿病视网膜病变（DR）和糖尿病肾病（DN）保护因子的鉴定可以提供重要的生物标志物和治疗剂，以预防和阻止这两种毒性并发症显著降低生活质量。使用一个独特的1型糖尿病（T1 DM）患者超过50年的疾病（Medalists）的人口，我们已经开始确定潜在的保护因素，DR和DN通过前和死后的研究。我们通过临床检查、混合餐耐受试验、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%没有或只有轻度DR（ETDRS <53），并且少于14%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，已经捐赠了超过16名奖牌研究参与者的尸检标本。视网膜、玻璃体和肾小球标本的蛋白质组图谱已经确定了DR和DN的第一组潜在保护因子。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。根据通路定位和文献综述，在肾小球分析中鉴定的14个候选蛋白质都参与燃料代谢。视网膜分析中确定的10个因素涉及膜回收、运输、光传导恢复和视网膜功能。生物信息学途径分析表明，DR的候选人与DN的候选人不重叠;然而，两组保护因素表明，与相应条件相比，无DR或DN的Medalists中存在更有活力和代谢活性的组织。本研究旨在测量Medalists和另一组不寻常的超快速进展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，将在培养的DR和DN的视网膜血管和肾小球和肾小管细胞模型中研究保护免受高血糖暴露的能力。我们还将能够确定这些潜在的保护因子在细胞培养模型和体内糖尿病动物模型中的生物学作用。通过这些转化研究，我们将能够识别和确认与DR和DN相关的潜在保护因素。