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

• 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
• 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

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（T1 D）是一种自身免疫性疾病，其中胰腺的产生胰岛素的β细胞被破坏。 摧毁.这些β细胞被自身反应性T细胞特异性地靶向破坏， 逃避胸腺中的正常消除机制。虽然很明显，除了环境 由于涉及强大的遗传成分，自身免疫性T1 D的潜在基础并不清楚， 明白包括T1 D在内的许多疾病的GWAS最近突出了调控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T1 D基因型-表型因果关系的分子机制。我们 总体目标是深入表征DNA调控元件及其风险变体， 在分子和功能水平上构成T1 D易感性的基础。 我们的中心假设是，T1 D相关的SNP改变了细胞类型特异性DNA调控的功能， 元素在强有力的初步数据的指导下，我们将从3个互补的角度来探讨这一假设： 我们将使用最先进的和新颖的计算策略来精细映射T1 D GWAS SNP到候选人。 因果变量（目标1）。我们将通过利用一个新的方法来描述因果候选SNP的作用机制。 功能基因组学和蛋白质组学的结合（目的2）。最后，我们将确定功能相关性 T1 D相关人类系统中的因果变异（目标3）。 这种方法是高度创新的，将提供第一个深入的DNA功能表征 调节元件及其风险变异是T1 D易感性的基础。我们的研究将提供一个重要的 从人类T1 D易感性的相关性研究转向功能性研究。最终，这些知识 有可能转化为新的方法来预测，预防和潜在地治疗T1 D。