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Functional Interrogation of T2D-associated genes in human stem cell-derived models and mice

人类干细胞衍生模型和小鼠中 T2D 相关基因的功能研究

基本信息

批准号：
10242941
负责人：
Struan F A Grant
金额：
$ 184.36万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-20 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10242941
关键词：
ATAC-seq Adipocytes Affect Animals Area Biological Biological Process Biology Biometry Blindness Candidate Disease Gene Cardiovascular Diseases Cause of Death Cell model Cells Chronic Collaborations Collection Communities Complex Data Data Set Diabetes Mellitus Diabetic mouse Disease Disease model Disease susceptibility Engineering Functional disorder Funding Gene Targeting Genes Genetic Genetic Engineering Genetic Predisposition to Disease Genetic study Genomic approach Genomics Goals Health Hepatocyte Heterogeneity Human Human Genetics Hyperglycemia Individual Insulin Resistance Investigation Kidney Failure Knowledge Liver Malignant Neoplasms Metabolic Methods Modeling Molecular Mus Muscle Fibers Mutant Strains Mice Neuropathy Non-Insulin-Dependent Diabetes Mellitus Obesity Pancreas Pathway Analysis Pathway interactions Patients Pediatric Hospitals Pennsylvania Phenotype Philadelphia Physiological Population Genetics Positioning Attribute Predisposition Prevalence Process Regulation Regulator Genes Research Resources Role Skeletal Muscle Source Structure of beta Cell of islet System Testing Therapeutic Tissue Banks Tissues Transcript United States National Institutes of Health Universities Untranslated RNA Variant Veterans biobank bioinformatics pipeline causal variant cell type chromosome conformation capture clinical translation computational pipelines conditional mutant diabetes pathogenesis follow-up functional genomics genome wide association study genome-wide genomic data genomic locus human stem cells human tissue in vivo induced pluripotent stem cell loss of function molecular phenotype mouse model multidisciplinary multiple data sources mutant mutant mouse model new therapeutic target novel therapeutics overtreatment programs stem cell model stem cells therapeutic target trait transcriptome sequencing

项目摘要

Functional Interrogation of T2D-associated genes in human stem cell-derived models and mice Type 2 Diabetes (T2D) is one of the fastest-growing diseases and a leading cause of death throughout the world. A better understanding of the disease process, including characterization of both the genetic etiology and the contribution of different cell types to disease initiation, progression and heterogeneity promises to reveal new therapeutic targets. Large-scale genome-wide association studies (GWAS) of this common complex trait have driven the rapid identification of hundreds of T2D-associated loci. However, the mechanism(s) through which most of these loci influence disease susceptibility remain poorly understood. Our interdisciplinary team at Penn brings together experts in population genetics, T2D GWAS, biostatistics, metabolic tissue biology, human cellular disease modeling and T2D pathophysiology to tackle this critical knowledge gap. In collaboration with other Consortium groups, we aim to accomplish the following goals. (1) Provide the diabetes research community with a robust pipeline for mapping T2D GWAS variants to effector genes and target tissues. (2) Identify new genes and biological pathways that modulate susceptibility to T2D. (3) Define gene regulatory networks relevant to T2D with the goal of uncovering therapeutic ‘entry points’ for developing new treatments. For (1), we will prioritize “candidate effector transcripts” for downstream functional analyses by integrating multiple sources of data to gain a ‘confluence of evidence’ as to their disease relevance and tissue of action. These sources include publically available datasets, a unique collection of internal resources from the Million Veteran Program, and our own functional genomics (RNA-seq, ATAC-seq, chromatin conformation capture etc.) data generated from stem cell-derived T2D relevant cell types. For (2), we will examine the biological function of prioritized T2D-effector transcripts in human cell models of T2D-relevant tissue types using gain- and loss-of- function methods combined with a battery of physiological, metabolic, molecular phenotyping and genomic approaches. These studies include the use of induced pluripotent stem cell (iPSC) models for pancreatic b cells, hepatocytes, adipocytes and skeletal muscle cells, enabling precise genetic engineering and establishment of multiple cell types in the same genetic background. Through this process, we will identify 10 high priority candidate effector genes, which we will advance for comprehensive in vivo analyses in conditional mutant mouse models. For (3), we will perform network analyses through the integration of our multiple data sources to identify molecular memberships in broader pathways and search for pathway components that are potentially amenable for therapeutic targeting.

t2d相关基因在人类干细胞衍生模型和小鼠中的功能研究