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：
8241364
负责人：
GEORGE L KING
金额：
$ 396.36万
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/8241364
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 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. PUBLIC HEALTH RELEVANCE: Clinically, studies in diabetic patients who have survived greater than 50 years of disease duration clearly have demonstrated that endogenous protective factors can prevent and delay for extreme periods of time the onset of diabetic microvascular complications. Thus, therapeutic approach in the future for diabetic vascular complications needs to decrease the toxic effects of hyperglycemia as well as increase the actions of protective/survival factors in order to be effective.

描述（由申请人提供）：鉴定糖尿病性视网膜病（DR）和糖尿病性肾病（DN）的保护因素可以提供重要的生物标志物和治疗剂，以预防和停止这两种有毒并发症，从而显着降低生活质量。使用超过50年的疾病（奖章）的1型糖尿病患者（T1DM）的独特群体，我们已经开始通过Mortem研究来确定DR和DN的潜在保护因素。我们通过临床检查，混合进餐测试，广泛的眼科检查和病史问卷来广泛表征600多名奖牌获得者。令人惊讶的是，35％的人没有或仅有轻度DR（ETDR <53），少于14％的DN（ACR <70 mcg/mg）。事后组织学检查证实了这些发现。到目前为止，已经捐赠了16多名奖牌研究参与者的验尸后标本。来自视网膜，玻璃体和肾肾小球的标本的蛋白质组学映射已经确定了DR和DN的第一组潜在保护因子。这是通过比较受影响组织和未影响组织之间的蛋白质表达来完成的。根据途径映射和文献综述，在肾小球分析中鉴定的十四种候选蛋白都参与燃料代谢。视网膜分析中确定的10个因素涉及膜回收，传输，光转导的回收和视网膜功能。生物信息学途径分析表明，确定为DR的候选者与DN的候选者不会重叠。然而，两组保护因素都表明，与具有各自条件的奖章相比，没有DR或DN的奖章者中存在更多的活性和代谢活性组织。这项研究建议在奖章者和另一个具有超快速进展的糖尿病患者组中的等离子体和循环细胞中的所有已鉴定和验证的候选者。此外，将在培养的DR和DN的培养的视网膜血管和肾小球和管状细胞模型中研究预防高血糖暴露的能力。在细胞培养模型和糖尿病的体内动物模型中，我们还将能够确定这些潜在保护因素的生物学作用。从这些翻译研究中，我们将能够识别并确认与DR和DN相关的潜在保护因素。公共卫生相关性：从临床上讲，对超过50年疾病持续时间存活的糖尿病患者的研究清楚地表明，内源性保护因素可以预防和延迟极端的糖尿病微血管并发症的发作。因此，未来的糖尿病血管并发症的治疗方法需要降低高血糖的毒性作用，并增加保护性/生存因子的作用，以便有效。