Deciphering the molecular basis of T1D in human cells using functional genomics

使用功能基因组学解读人类细胞中 T1D 的分子基础

基本信息

批准号：
9228681
负责人：
STEVEN A CARR
金额：
$ 416.03万
依托单位：
HARVARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-30 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9228681
关键词：
Address Affect Affinity Alleles Antigen Presentation Pathway Autoimmune Diseases Autoimmune Process Beta Cell Binding Binding Sites Bioinformatics Biological Assay Biology Cell physiology Cells Cellular Stress ChIP-seq Code Computer Simulation DNA DNA-Binding Proteins Data Data Set Diagnostic Disease Dissection Distal Elements Enhancers Environment Environmental Risk Factor Etiology Functional disorder Gene Expression Regulation Gene Targeting Genes Genetic Genetic Variation Genome engineering Genotype Glucose Goals Hematopoietic System Hot Spot Human Individual Insulin Insulin-Dependent Diabetes Mellitus Investigation Knowledge Lead Link Maps Mediating Modeling Molecular Molecular Mechanisms of Action Mutagenesis Open Reading Frames Organ Specificity Pathology Pattern Phenotype Physiological Pluripotent Stem Cells Population Predisposition Prevention Proteins Proteomics Public Health Regulator Genes Regulatory Element Reporter Research Single Nucleotide Polymorphism Structure of beta Cell of islet System Testing Thymic epithelial cell Thymus Gland Transcriptional Regulation Translating Untranslated RNA Variant abstracting autoreactive T cell base cell type chromatin modification chromosome conformation capture effective therapy epigenomics functional genomics gene function genome wide association study human stem cells humanized mouse improved innovation insight novel novel strategies prevent risk variant stem cell biology tool transcription factor transcriptome sequencing transcriptomics

项目摘要

Project Abstract Type 1 Diabetes (T1D) is an autoimmune disease in which the insulin-producing beta cells of the pancreas are destroyed. These beta cells are specifically targeted for destruction by autoreactive T cells, which manage to escape the normal elimination mechanisms in the thymus. Although it is clear that besides environmental factors a strong genetic component is involved, the underlying basis for autoimmune T1D is not well understood. GWAS for a number of diseases, including T1D, have recently highlighted regulatory DNA regions rather than protein coding sequences as "hot spots" where single nucleotide polymorphisms (SNPs) as causal variants can be found. Our long term goal is to decipher the molecular mechanism of genotype-phenotype causalities in T1D. Our overall objective is the in depth characterization of DNA regulatory elements and their risk variants that underlie T1D susceptibility on a molecular and functional level. Our central hypothesis is that T1D associated SNPs alter the function of cell type-specific DNA regulatory elements. Guided by strong preliminary data, we will approach this hypothesis from 3 complementary angles: We will use state-of-the-art and novel computational strategies to fine map T1D GWAS SNPs to candidate causal variants (Aim 1). We will characterize the mechanism of action of causal candidates SNPs by utilizing a combination of functional genomics and proteomics (Aim 2). Finally, we will determine the functional relevance of causal variants in T1D-relevant human(-ized) systems (Aim 3). This approach is highly innovative and will provide the first in depth functional characterization of DNA regulatory elements and their risk variants that underlie T1D susceptibility. Our studies will provide a significant shift from the correlative to the functional investigation of human T1D susceptibility. Ultimately, such knowledge has the potential to translate to novel approaches to predict, prevent and potentially to treat T1D.

项目摘要 1型糖尿病（T1D）是一种自身免疫性疾病，其中胰腺的产生胰岛素β细胞为被摧毁。这些β细胞专门针对自动反应性T细胞的破坏，该细胞设法避开胸腺中正常的消除机制。虽然很明显，除了环境之外因素涉及强大的遗传成分，自身免疫性T1D的基本基础不好理解。包括T1D在内的多种疾病的GWA，最近强调了调节性DNA区域而不是蛋白质编码序列作为“热点”，其中单核苷酸多态性（SNP）作为因果关系可以找到变体。我们的长期目标是破译T1D基因型 - 表型因果关系的分子机制。我们的总体目标是DNA调节元件及其风险变异的深入表征， T1D的基础在分子和功能水平上。我们的中心假设是T1D相关的SNP改变了细胞类型特异性DNA调节的功能元素。在强大的初步数据的指导下，我们将从3个互补角度来解决这一假设：我们将使用最先进和新颖的计算策略来细微地图T1D GWAS SNP候选因果变体（AIM 1）。我们将通过使用A来表征因果候选者SNP的作用机理功能基因组学和蛋白质组学的组合（AIM 2）。最后，我们将确定功能相关性与T1D相关的人类（-ized）系统（AIM 3）中的因果变异。这种方法具有很高的创新性，将提供DNA的第一个深度功能表征 T1D敏感性的基础的监管要素及其风险变体。我们的研究将提供重要的从相关性转向人类T1D易感性的功能研究。最终，这样的知识有可能转化为预测，预防和潜在处理T1D的新方法。