Identifying urinary biomarkers for early type 2 diabetic nephropathy

识别早期 2 型糖尿病肾病的尿液生物标志物

基本信息

批准号：
8723164
负责人：
Maryam Afkarian
金额：
$ 14.9万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-15 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8723164
关键词：
Age Albuminuria Biological Biological Assay Biological Markers Blood Pressure Calibration Candidate Disease Gene Caring Clinical Clinical Data Commit Data Development Diabetes Mellitus Diabetic Nephropathy Diagnosis Diagnostic Disadvantaged Disease Disease Progression Doctor of Philosophy Early Diagnosis Early identification End stage renal failure Enzyme-Linked Immunosorbent Assay Experimental Designs Functional disorder Future General Hospitals Generations Hospitals Injury Internal Medicine Joints Kidney Kidney Diseases Kidney Failure Light Longitudinal Studies Mass Spectrum Analysis Massachusetts Measures Medical Medical center Mentors Microalbuminuria Nephrology New York Non-Insulin-Dependent Diabetes Mellitus Pathway interactions Patients Pattern Peptides Phase Phenotype Plasma Proteins Population Population Study Presbyterian Church Proteins Proteinuria Proteomics Race Relative (related person)Renal dialysis Renal function Research Research Design Research Personnel Residencies Resources Risk Sampling Specificity Staging Supplementation Surface Technology Testing Therapeutic Time Training Universities Urine Variant Washington Woman base career development case control clinical Diagnosis cohort comparative design diabetic disease diagnosis disease natural history effective therapy follow-up improved instructor ionization mRNA Expression multiple reaction monitoring novel diagnostics novel marker novel therapeutics programs public health relevance research study sex stable isotope success tool urinary

项目摘要

DESCRIPTION (provided by applicant): Candidate: Maryam Afkarian received an MD-PhD from Washington University in St. Louis and underwent residency training in Internal Medicine at New York Presbyterian Hospital-Weill Cornell Medical Center. She is currently a Nephrology Research Fellow at the joint program of Massachusetts General Hospital and Brigham and Women's Hospital. Starting July 2010, she will be appointed as an instructor at the Nephrology Division of Massachusetts General Hospital. Mentor: Dr. Ravi Thadhani is an internationally recognized clinical and translational investigator with a strong track record of mentoring new investigators. He is, and will remain, a closely-involved mentor, committed to the success of Dr. Afkarian's training, her proposed studies and career development. Research: Diabetic nephropathy (DN) is the leading cause of end-stage kidney disease. However, with the current standards of care, we can only delay progression of this disease. This is partly due to a lack of effective therapies and partly due to absence of reliable assays for diagnosis of the early disease, before renal damage is severe or irreversible. New diagnostic and therapeutic tools are urgently needed, both of which require an improved understanding of the disease natural history, i.e. identification of new markers of onset and progression. Comparative proteomic analysis of urine (study of the urine protein composition and how it is changed in the disease state) has been used to identify markers for several kidney diseases. Dr. Thadhani (mentor)'s group has previously used this approach to identify a peptide signature that detected signs of early diabetic kidney injury up to 10 years prior to clinical diagnosis. This proposal lays out a multi-stage approach to identify the proteins that are altered in early DN. The preliminary data describes calibration and adaptation of a sensitive proteomic technology (iTRAQ: isobaric Tags for Relative and Absolute Quantitation) for application to urine. In Aim 1A, iTRAQ will be used to compare urine samples from patients with and without DN (cases and controls, respectively). This hypothesis-free and unbiased comparative analysis will generate a preliminary list of candidate biomarkers for early DN. In Aim 1B, this list will be supplemented with hypothesis-driven candidates, i.e. those with significant evidence of involvement in DN. Examples are proteins which (a) are part of pathways incriminated in DN, (b) have altered mRNA expression in DN or (c) have altered protein level in DN. This step serves to incorporate all currently available information into this biomarker discovery effort. In Aim 3, a target-specific and quantitative assay, e.g. ELISA, is used to re-evaluate the expression of putative biomarkers from Aims 1A and 1B in an independent cohort. This step will help weed out the false positives and identify a subset of markers whose differential expression in DN is confirmed. In Aim 4, the expression of these confirmed markers will be characterized over the course of disease. This proposal is designed to generate a group of candidate biomarkers for early DN which have been validated within the original study population. A future step would be to test these candidates in a broader and more varied population. In long term, we hope that the validated biomarkers would serve as a novel diagnostic tool for early DN and also help shed light on the disease pathophysiology.

描述（由申请人提供）：候选人：Maryam Afkarian获得了圣路易斯华盛顿大学的MD-PHD，并接受了纽约长老会医院 - 康奈尔医疗中心的内科住院医师培训。她目前是马萨诸塞州综合医院联合计划以及杨百翰和妇女医院的肾脏病研究研究员。从2010年7月开始，她将被任命为马萨诸塞州综合医院肾脏病科教练。导师：Ravi Thadhani博士是国际认可的临床和转化研究者，具有指导新研究人员的良好记录。他是并且将仍然是一位紧密涉及的导师，他致力于阿夫卡里安（Afkarian）培训，她的拟议学习和职业发展的成功。研究：糖尿病性肾病（DN）是终末期肾脏疾病的主要原因。但是，按照目前的护理标准，我们只能延迟这种疾病的进展。这部分是由于缺乏有效的疗法，部分原因是由于缺乏可靠的测定方法来诊断早期疾病，然后肾脏损害是严重或不可逆的。迫切需要新的诊断和治疗工具，这两者都需要对疾病自然史的了解，即确定发作和进展的新标志。尿液的比较蛋白质组学分析（尿蛋白组成的研究及其在疾病状态下的变化）已被用于鉴定多种肾脏疾病的标志物。 Thadhani博士（导师）的小组先前已经使用了这种方法来识别肽签名，该肽签名在临床诊断之前检测到长达10年的早期糖尿病肾脏损伤迹象。该提案提出了一种多阶段方法来识别早期DN改变的蛋白质。初步数据描述了用于应用于尿液的敏感蛋白质组学技术的校准和适应性（用于相对和绝对定量的等速标签）。在AIM 1A中，ITRAQ将用于比较有或没有DN患者（分别为病例和对照）的患者的尿液样本。这种假设无偏见的比较分析将产生早期DN的候选生物标志物的初步列表。在AIM 1B中，该列表将补充假设驱动的候选人，即具有大量参与DN的证据的候选人。例子是蛋白质（a）是DN中犯罪途径的一部分，（b）在DN或（C）中的mRNA表达改变改变了DN中的蛋白质水平。此步骤将所有当前可用的信息纳入此生物标志物发现工作中。在AIM 3中，目标特异性和定量测定，例如ELISA用于重新评估独立队列中AIMS 1A和1B的假定生物标志物的表达。此步骤将有助于淘汰误报，并确定确认DN中差异表达的标记子集。在AIM 4中，这些确认的标记的表达将在整个疾病过程中被表征。该建议旨在为早期DN生成一组候选生物标志物，这些生物标志物已在原始研究人群中得到验证。未来的一步是在更广泛，更多样化的人群中测试这些候选人。从长远来看，我们希望经过验证的生物标志物能够成为早期DN的新型诊断工具，并有助于阐明疾病的病理生理学。