Epigenetic drivers and biomarkers of diabetic kidney disease

糖尿病肾病的表观遗传驱动因素和生物标志物

基本信息

批准号：
9037336
负责人：
KATALIN SUSZTAK
金额：
$ 239.2万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-25 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9037336
关键词：
Acetates Animal Model Base Sequence Biological Markers Blood Blood specimen Cell division Cells Chromatin Chronic Kidney Insufficiency Comprehension Cytosine DNA Data Development Diabetes Mellitus Diabetic Nephropathy Diagnostic Disease Progression Endothelial Cells Enhancers Enrollment Environment Enzymes Epigenetic Process Epithelial Cells Excess Mortality Fibrosis Future Gene Expression Gene Expression Profile Generations Genetic Genetic Polymorphism Glucose Heritability Histones Human Hypertension Inflammatory Response Inherited Injury Insulin-Dependent Diabetes Mellitus Kidney Kidney Diseases Kidney Glomerulus Life Expectancy Link Metabolic Metabolic Control Metabolism Methionine Methylation Modification Mus NF-kappa B Nutritional Outcome Pathogenesis Patients Phenotype Play Renal function Renal tubule structure Reporting Role Sampling Sequence Analysis Statistical Methods Subgroup Surveys System Tail Tissues Transcript Transferase Tubular formation Untranslated RNA Variant cell type cohort cost defined contribution environmental change epigenome genome-wide glycemic control in vivo meetings methylation pattern new therapeutic target novel novel diagnostics programs public health relevance repaired transcription factor

项目摘要

DESCRIPTION: Diabetes (DM) shortens life expectancy by about 10 years. Renal disease shows the strongest correlation with excess mortality, yet our comprehension of diabetic kidney disease (DKD) remains limited. Epigenetics refers to heritable changes in gene expression patterns that are not caused by alterations in the nucleotide sequence itself. The epigenetic system is heritable and reversible at the cellular level. Cytosine modifications fully meet these criteria. Other factors including: histone tail modifications, higher order chromatin organization and long and short non-coding RNA molecules are often described as epigenetic mechanisms, but they not fulfill all criteria as epigenetic mechanism. Several lines of evidence point to the epigenome as an important missing link in our understanding of DKD pathogenesis. The hypothesis of the proposal is that cytosine methylation changes reflect long-term prior metabolic alterations. Epigenetic differences can subgroup DKD patients and can predict kidney function decline by influencing transcript level changes. Under this proposal we plan to: 1. Characterize genome-wide cytosine methylation patterns in 800 microdissected human kidney TEC; including controls (in absence of diabetes, hypertension and normal kidney function), patients with diabetes or hypertension and absence of renal disease and patients with CKD in the setting of hypertension and compare them to DKD samples. 2. Define the contribution of cytosine methylation changes to phenotype development. Define the association between cytosine methylation and gene expression changes using novel statistical methods. 3. Understand whether cytosine methylation changes can be used to predict GFR course in the CRIC cohort, by comparing cytosine methylation changes of patients with rapidly vs. slowly progressive DKD upon enrollment.

描述：糖尿病（DM）将预期寿命缩短约10年。肾脏疾病表明与过度死亡率有很强的相关性，但是我们对糖尿病肾脏疾病（DKD）的理解仍然有限。表观遗传学是指基因表达模式的可遗传变化，而基因表达模式并非是由核卫星序列本身改变引起的。表观遗传系统在细胞水平上是可遗传的和可逆的。胞嘧啶修饰完全符合这些标准。其他因素包括：组蛋白的尾巴修饰，高阶染色质组织以及长而短的非编码RNA分子通常被描述为表观遗传机制，但它们不能满足所有标准作为表观遗传机制。几条证据表明，表观基因组是我们对DKD发病机理的理解中的重要缺失联系。该提议的假设是胞嘧啶甲基化变化反映了长期的先前代谢改变。表观遗传学差异可以亚组DKD患者，并且可以通过影响转录水平变化来预测肾功能下降。在此提案下，我们计划：1。在800个微解析的人肾脏TEC中的全基因组胞嘧啶甲基化模式表征；包括对照（在没有糖尿病的情况下，高血压和正常肾功能），患有糖尿病或高血压的患者以及肾脏疾病的缺乏以及在高血压的情况下患有CKD患者，并将其与DKD样品进行比较。 2。定义胞嘧啶甲基化对表型发育的贡献。定义使用新型统计方法变化的胞嘧啶甲基化和基因表达变化之间的关联。 3。了解胞嘧啶甲基化变化是否可以通过比较入学时快速与缓慢进行性DKD的患者的胞嘧啶甲基化变化来预测CRIC队列中的GFR课程。