Biomarkers in Diabetic Neuropathy

糖尿病神经病变的生物标志物

• 批准号: 7812489
• 负责人: Eva Lucille Feldman
• 金额: $ 25.56万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7812489
• 关键词: Affect; American; Animal Model; Area; Behavior; Biochemical Pathway; Bioinformatics; Biological; Biological Markers; Biomedical Research; Biopsy; Clinical Treatment; Clinical Trials; Complex; Complication; Complications of Diabetes Mellitus; Data; Data Set; Development; Diabetes Mellitus; Diabetic Neuropathies; Diagnosis; Disease; Disease model; Dyslipidemias; Environment; Event; Fiber; Figs - dietary; Gene Expression; Gene Expression Profiling; Gene Proteins; Gene Targeting; Generations; Genes; Goals; Human; Hypertriglyceridemia; Incidence; Lead; Left; Lipids; Liquid substance; Measurable; Measures; Metabolic; Metabolic Marker; Methods; Michigan; Modeling; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Neural Conduction; Non-Insulin-Dependent Diabetes Mellitus; Onset of illness; Pathway interactions; Patients; Pattern; Peripheral Nerves; Peripheral Nervous System Diseases; Plasma; Process; Proteins; Protocols documentation; Public Health; Regulation; Research; Sampling; Sensory; Serum; Systems Biology; Therapeutic; Tissues; United States National Institutes of Health; Universities; Urine; Validation; Western Blotting; biological systems; biomedical informatics; cell growth regulation; clinically relevant; db/db mouse; density; disorder risk; in vivo Model; interest; lipid metabolism; macromolecule; neurophysiology; novel; protein metabolite; public health relevance; response; sciatic nerve; single molecule; sural nerve; transcriptomics

DESCRIPTION (provided by applicant): Challenge Area: (03) Biomarker Discovery and Validation Challenge Topic: Discovery of biomarkers for disease risk, progression or response to therapy in diseases of interest to NIDDK. 03-DK-101 Title: Biomarkers in Diabetic Neuropathy Twenty million Americans have diabetes and the incidence is increasing by 5% per year. The most common complication of diabetes is diabetic neuropathy (DN). Current methods used to confirm DN and measure its progression include nerve conduction studies, quantitative sensory measures and decreased sural nerve myelinated fiber density (MFD). The identification of DN biomarkers would greatly enhance our understanding of early events in this complication and could be used to predict its development and rate of progression. No biomarkers have been established for DN leaving this complication to develop unchecked. We hypothesize that a complex network of metabolic changes in type 2 diabetes may predict the onset and progression of DN. Bioinformatics protocols applied to metabolic, neuroanatomical and neurophysiology data from a clinical trial of DN indicate that dyslipidemia, specifically elevated triglyceride levels, is associated with rapid progression of DN. The current proposal employs microarray analyses to examine differentially expressed genes involved in lipid metabolism in both human sural nerve samples and in peripheral nerves from a relevant animal model, the BKS-db/db mouse. Our membership in the National Center for Integrated Biomedical Informatics (NCIBI) at the University of Michigan provides us with a high-powered computing environment and the expertise for computationally intensive analyses. We have two Specific Aims: Hypothesis 1: The application of bioinformatics will identify targets (genes, proteins and metabolic markers) involved in the initiation and progression of DN. Specific Aim 1: Identify genes of interest regulated across species in DN. a. Use microarrays to identify biomarker pathways and targets in human sural nerve samples from patients with type 2 diabetes and DN. b. Perform cross-species validation between sciatic nerve microarrays from mice with type 2 diabetes and the human sural nerve microarrays in Aim 1a. Hypothesis 2: Verified transcriptomics will predict changes in encoded proteins (in peripheral nerve) and metabolites (in plasma and urine) critical to the initiation and progression of DN in human patients and animal models. These functional responses will lead to the identification of biomarkers useful in the diagnosis and therapeutic management of human DN. Specific Aim 2: Validate the biological relevance of identified gene targets in a type 2 murine model with DN a. Localize and quantify target gene products (proteins) in sciatic nerve using immunolocalization and western blotting b. Identify and examine metabolite levels in biological fluids (plasma and urine) PUBLIC HEALTH RELEVANCE: The most common complication of diabetes is peripheral neuropathy (DN). The identification of DN biomarkers would greatly enhance our understanding of early events in this complication and could be used to predict its development and rate of progression. We hypothesize that diabetes directly affects peripheral nerve gene expression and that these data will aid in the identification of useful DN biomarkers. Microarray analyses will compare changes in gene expression between human sural nerve biopsies and BKS-db/db mice, a well-researched model of type 2 diabetes. These data will be used to identify dysregulated intracellular pathways that would result in detectable biomarkers of DN in serum or urine and changes in expression following treatment in animal models.

描述（由申请人提供）： 挑战领域：(03)生物标志物发现和验证 挑战主题：发现 NIDDK 感兴趣的疾病风险、进展或治疗反应的生物标志物。 03-DK-101 标题：糖尿病神经病变的生物标志物 2000 万美国人患有糖尿病，并且发病率每年以 5% 的速度增加。糖尿病最常见的并发症是糖尿病神经病变（DN）。目前用于确认 DN 并测量其进展的方法包括神经传导研究、定量感觉测量和腓肠神经有髓纤维密度 (MFD) 降低。 DN 生物标志物的鉴定将极大地增强我们对这种并发症早期事件的理解，并可用于预测其发展和进展速度。尚未建立 DN 的生物标志物，导致这种并发症的发展不受控制。我们假设 2 型糖尿病代谢变化的复杂网络可以预测 DN 的发病和进展。应用于 DN 临床试验的代谢、神经解剖学和神经生理学数据的生物信息学方案表明，血脂异常，特别是甘油三酯水平升高，与 DN 的快速进展相关。目前的提案采用微阵列分析来检查人类腓肠神经样本和相关动物模型（BKS-db/db 小鼠）周围神经中参与脂质代谢的差异表达基因。我们是密歇根大学国家综合生物医学信息学中心 (NCIBI) 的成员，为我们提供了高性能的计算环境和计算密集型分析的专业知识。我们有两个具体目标： 假设1：生物信息学的应用将识别参与DN发生和进展的靶点（基因、蛋白质和代谢标志物）。 具体目标 1：确定 DN 中跨物种调控的感兴趣基因。一个。使用微阵列识别 2 型糖尿病和 DN 患者的人类腓肠神经样本中的生物标志物通路和靶点。 b.在目标 1a 中，对 2 型糖尿病小鼠的坐骨神经微阵列和人类腓肠神经微阵列进行跨物种验证。 假设 2：经过验证的转录组学将预测编码蛋白（周围神经中）和代谢物（血浆和尿液中）的变化，这些变化对于人类患者和动物模型中 DN 的发生和进展至关重要。这些功能反应将有助于鉴定出可用于人类 DN 诊断和治疗管理的生物标志物。 具体目标 2：在 2 型 DN 小鼠模型中验证已识别基因靶标的生物学相关性 一个。使用免疫定位和蛋白质印迹定位和量化坐骨神经中的靶基因产物（蛋白质） b.识别和检查生物体液（血浆和尿液）中的代谢物水平 公众健康相关性：糖尿病最常见的并发症是周围神经病变 (DN)。 DN 生物标志物的鉴定将极大地增强我们对这种并发症早期事件的理解，并可用于预测其发展和进展速度。我们假设糖尿病直接影响周围神经基因表达，这些数据将有助于识别有用的 DN 生物标志物。微阵列分析将比较人类腓肠神经活检和 BKS-db/db 小鼠（一种经过充分研究的 2 型糖尿病模型）之间基因表达的变化。这些数据将用于识别失调的细胞内通路，从而导致血清或尿液中可检测到的 DN 生物标志物以及动物模型治疗后表达的变化。