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

• 批准号: 10649538
• 负责人: Struan F A Grant
• 金额: $ 174.17万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 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/10649538
• 关键词: ATAC-seq; Ablation; 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; 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; Maps; 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; Research; Resources; Role; Skeletal Muscle; Source; Structure of beta Cell of islet; System; Testing; Therapeutic; Tissues; Transcript; United States National Institutes of Health; Universities; Untranslated RNA; Variant; Veterans; biobank; bioinformatics pipeline; candidate identification; causal variant; cell type; chromosome conformation capture; clinical translation; computational pipelines; conditional mutant; diabetes pathogenesis; follow-up; functional genomics; gain of function; gene interaction; gene network; gene regulatory network; 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; programs; stem cell model; stem cells; therapeutic target; trait; transcriptome sequencing

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.

在人类干细胞衍生模型和小鼠中对T2D相关基因的功能询问 2型糖尿病（T2D）是全世界增长最快的疾病之一，也是死亡的主要原因。 更好地了解疾病过程，包括遗传病因和 不同细胞类型对疾病起始，进展和异质性的贡献有望揭示新的 治疗靶标。这个共同复杂性状的大规模基因组关联研究（GWAS）具有 驱动了数百个T2D相关的网站的快速鉴定。但是，通过 这些局部影响疾病的易感性中的大多数仍然了解得很糟糕。我们在宾夕法尼亚的跨学科团队 汇集了人群遗传学，T2D GWA，生物统计学，代谢组织生物学，人类细胞的专家 疾病建模和T2D病理生理学，以应对这一关键知识差距。与其他 财团小组，我们旨在实现以下目标。 （1）为糖尿病研究界提供了强大的管道，用于将T2D GWAS变体映射到 效应子基因和目标时机。 （2）确定调节T2D易感性的新基因和生物学途径。 （3）定义与T2D相关的基因调节网络，目的是发现治疗 为开发新治疗的积分。 对于（1），我们将优先考虑“候选效应子成绩单”，以通过集成来进行下游功能分析 多种数据来源，以获得有关其疾病相关性和作用组织的“证据汇合”。 这些来源包括公开可用的数据集，这是百万的独特内部资源集合 资深计划和我们自己的功能基因组学（RNA-SEQ，ATAC-SEQ，染色质构象捕获等） 由干细胞衍生的T2D相关细胞类型产生的数据。对于（2），我们将检查 在T2D相关组织类型的人类细胞模型中优先考虑的T2D效应器转录本，使用增长和丧失 功能方法与一系列生理，代谢，分子表型和基因组结合 方法。这些研究包括用于胰腺B细胞的诱导多能干细胞（IPSC）模型， 肝细胞，脂肪细胞和骨骼肌细胞，使精确的遗传工程和建立 在相同的遗传背景中多种细胞类型。通过此过程，我们将确定10个高优先级 候选效应子基因，我们将在条件突变小鼠中进行全面的体内分析 型号。对于（3），我们将通过集成多个数据源进行网络分析以识别 在更广泛的途径中的分子成员资格，并寻找可能正常的途径成分 用于治疗靶向。

项目成果

Genomics and phenomics of body mass index reveals a complex disease network.

• DOI: 10.1038/s41467-022-35553-2
• 发表时间: 2022-12-29
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Huang, Jie;Huffman, Jennifer E.;Huang, Yunfeng;Do Valle, Italo;Assimes, Themistocles L.;Raghavan, Sridharan;Voight, Benjamin F.;Liu, Chang;Barabasi, Albert-Laszlo;Huang, Rose D. L.;Hui, Qin;Nguyen, Xuan-Mai T.;Ho, Yuk-Lam;Djousse, Luc;Lynch, Julie A.;Vujkovic, Marijana;Tcheandjieu, Catherine;Tang, Hua;Damrauer, Scott M.;Reaven, Peter D.;Miller, Donald;Phillips, Lawrence S.;Ng, Maggie C. Y.;Graff, Mariaelisa;Haiman, Christopher A.;Loos, Ruth J. F.;North, Kari E.;Yengo, Loic;Smith, George Davey;Saleheen, Danish;Gaziano, J. Michael;Rader, Daniel J.;Tsao, Philip S.;Cho, Kelly;Chang, Kyong-Mi;Wilson, Peter W. F.;Sun, Yan, V;O'Donnell, Christopher J.
• 通讯作者: O'Donnell, Christopher J.

Multi-phenotype analyses of hemostatic traits with cardiovascular events reveal novel genetic associations.

• DOI: 10.1111/jth.15698
• 发表时间: 2022-06
• 期刊: Journal of thrombosis and haemostasis : JTH

Dietary Vitamin E Intake Is Associated With a Reduced Risk of Developing Digestive Diseases and Nonalcoholic Fatty Liver Disease.

• DOI: 10.14309/ajg.0000000000001726
• 发表时间: 2022-06-01
• 期刊: The American journal of gastroenterology

The Diabetes Syndrome - A Collection of Conditions with Common, Interrelated Pathophysiologic Mechanisms.

• DOI: 10.2147/ijgm.s305156
• 发表时间: 2021
• 期刊: International journal of general medicine
• 影响因子: 2.3
• 作者: Rachfal AW;Grant SFA;Schwartz SS
• 通讯作者: Schwartz SS

Variant-to-gene-mapping analyses reveal a role for pancreatic islet cells in conferring genetic susceptibility to sleep-related traits.

变异基因图谱分析揭示了胰岛细胞在赋予睡眠相关特征遗传易感性方面的作用。

• DOI: 10.1093/sleep/zsac109
• 发表时间: 2022
• 期刊: Sleep
• 影响因子: 5.6
• 作者: Lasconi,Chiara;Pahl,MatthewC;Pippin,JamesA;Su,Chun;Johnson,MatthewE;Chesi,Alessandra;Boehm,Keith;Manduchi,Elisabetta;Ou,Kristy;Golson,MariaL;Wells,AndrewD;Kaestner,KlausH;Grant,StruanFA
• 通讯作者: Grant,StruanFA