PTPN2 mutations affect islet beta cell susceptibility in T1D

PTPN2 突变影响 T1D 中胰岛β细胞的易感性

基本信息

批准号：
10614497
负责人：
LORI SUSSEL
金额：
$ 43.02万
依托单位：
UNIVERSITY OF COLORADO DENVER
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：
2020-07-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10614497
关键词：
Affect Alleles Autoimmune Autoimmunity B-Lymphocytes Beta Cell Biological Models CRISPR/Cas technology Cell Lineage Cell Survival Cell model Cell physiology Cells Cellular Metabolic Process Chronic Disease Complex Data Defect Development Disease Enzymes Event Functional disorder Genes Genetic Predisposition to Disease Glucose HLA Antigens High Fat Diet Human Immune Immune System Diseases Immune system Impairment Inbred NOD Mice Individual Inflammatory Insulin Insulin-Dependent Diabetes Mellitus Knock-out Knockout Mice Knowledge Mediating Metabolic Metabolic Pathway Minor Mitochondria Molecular Mus Mutation Pancreas Pathway interactions Patients Phenotype Predisposition Protein Tyrosine Phosphatase Pyruvate Kinase Regulation Research Role Signal Pathway Signal Transduction Single Nucleotide Polymorphism Streptozocin Stress Structure of beta Cell of islet System T-Lymphocyte T-cell protein tyrosine phosphatase Testing Tissue Sample Tissues Transgenic Mice Variant cytokine diabetes risk genetic variant genome wide association study human pluripotent stem cell inflammatory modulation insulin secretion islet mutant novel therapeutics prevent protein function response risk variant viral RNA

项目摘要

Type 1 diabetes (T1D) is characterized by the destruction of pancreatic beta cells by an individual’s own immune system. Although T1D is primarily viewed as a disease of the immune system, there is mounting evidence to suggest that insulin-producing β cells may actively contribute to their destruction. Furthermore, recent genome-wide association studies (GWAS) have suggested that although significant genetic predisposition to T1D is conferred by the human leukocyte antigen (HLA) complex, many single nucleotide polymorphisms (SNPs) in non-HLA loci also contribute to the disease {Floyel, 2015 #2}. Importantly, many of these non-HLA variants occur in genes expressed in both immune cell lineages as well as in the targeted β cells. Knowledge of how these minor gene variants affect function of islet b cells will allow us to develop novel therapies that could be effective in preventing progression of T1D. In this proposal, we will use transgenic mice and human b cell models to explore how mutations in the T1D risk allele Protein tyrosine phosphatase N2 (PTPN2), also known as T cell protein tyrosine phosphatase (TC-PTP), affect islet β cell function in the context of T1D and/or T1D mimicking conditions. In mice and humans, PTPN2 is broadly expressed in several tissues, including T cells and islet β cells, however mutations of PTPN2 have predominantly been studied in the T cell context. In mice, PTPN2 has been show to modulate inflammatory signaling in T cells by acting as a negative regulator of JAK/STAT signaling, downstream of a cytokine response. However, there is evidence that PTPN2-mediated autoimmunity cannot be fully explained by T cell dysfunction. T-cell specific inactivation of PTPN2 caused less severe autoimmune phenotypes than observed in global knockout mice. Indeed, in the pancreas, constitutive inactivation of PTPN2 impaired glucose stimulated insulin secretion in mice fed a high fat diet {Xi, 2015 #20}. The function of PTPN2 in β cells has not yet been examined in the context of T1D; however, PTPN2 is upregulated in mouse and human β cells upon treatment with proinflammatory cytokines or double stranded viral RNA, again suggesting an additional role for PTPN2 in islets. To parse out the β cell-specific contribution of PTPN2 mutations to T1D, we have generated a β cell-specific knockout of Ptpn2 (PTPN2-bKO). Our preliminary data indicate that metabolic pathways are altered in PTPN2-bKO islets under T1D mimicking stress conditions. Consistently, we have identified pyruvate kinase M2 (PKM2), an important glycolytic enzyme in the β cell to be a direct target of PTPN2. In addition, we have generated hPSCs deleted for PTPN2 and collected tissue samples from T1D individuals carrying mutations in PTPN2. In this proposal, we will test the hypothesis that disrupted function of PTPN2 in the β cell promotes the development of T1D by compromising β cell metabolic function and survival. In SA1 we will determine the beta cell defects associated with deletion of PTPN2 in basal and autoimmune-mediated conditions. In SA2 we will determine the molecular pathways regulated by PTPN2 in basal and autoimmune-mediated conditions.

1型糖尿病（T1D）的特征是胰腺β细胞通过个人的免疫系统的销售，作为免疫系统的速度，是由胰岛素产生的β细胞可能积极地促进其销售的。最近的全基因组关联研究（GWAS）表明，Allyooth遗传学捕食是由人类白细胞抗原（HLA）配合物赋予的。 2015＃2}在Get的β细胞中表达的许多非HLA变体将使我们能够在T1D中有效地发展Therat。 T1D风险等位基因蛋白质N2（PTPN2），也称为磷酸酪氨酸（TC-PTP），在T1D和/或T1D模仿条件下会影响胰岛β细胞融合。不可见量的T细胞和胰岛细胞，PTPN2的Howver突变已有22个为222是222是222是222，它是jak/stat信号的负调节剂，而细胞因子的下游是PTPN2介导的自动释放性的证据。 PTPN2的T细胞特异性灭活引起了与全球敲除小鼠相比，在胰腺中，PTPN2造成PTPN2造成的葡萄糖ED胰岛素分泌的小鼠的被征集灭活。在用促炎细胞因子或双链病毒RNA处理时，尚未在小鼠和人β细胞中检查PTPN2在β细胞中的功能，再次表明PTPN2在胰岛中的额外作用PTPN2突变对D的β细胞特异性贡献，我们具有PTPN2的β细胞特异性敲除（PTPN2-BKO）。 β细胞中的重要糖酵解酶是PTPN2的直接靶标。通过损害β细胞的代谢功能和生存率，我们将在基础和自身免疫介导的条件下用PTPN2定下的DETA细胞。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Modulation of insulin secretion by RBFOX2-mediated alternative splicing.

DOI：
10.1038/s41467-023-43605-4
发表时间：
2023-11-25
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Moss, Nicole D.;Wells, Kristen L.;Theis, Alexandra;Kim, Yong-Kyung;Spigelman, Aliya F.;Liu, Xiong;Macdonald, Patrick E.;Sussel, Lori
通讯作者：
Sussel, Lori

Not the second fiddle: α cell development, identity, and function in health and diabetes.

DOI：
10.1530/joe-22-0297
发表时间：
2023-08-01
期刊：
JOURNAL OF ENDOCRINOLOGY
影响因子：
4
作者：
Brooks, Elliott P.;Sussel, Lori
通讯作者：
Sussel, Lori

Found in Translation: Novel Insights Into Type 1 Diabetes and β-Cell Biology.

DOI：
10.2337/dbi21-0031
发表时间：
2021-10
期刊：
Diabetes
影响因子：
7.7
作者：
Russ HA;Davidson HW
通讯作者：
Davidson HW

Stem-Cell-Derived β-Like Cells with a Functional PTPN2 Knockout Display Increased Immunogenicity.

DOI：
10.3390/cells11233845
发表时间：
2022-11-30
期刊：
CELLS
影响因子：
6
作者：
Triolo, Taylor M. M.;Matuschek, J. Quinn;Castro-Gutierrez, Roberto;Shilleh, Ali H. H.;Williams, Shane P. M.;Hansen, Maria S. S.;McDaniel, Kristen;Barra, Jessie M. M.;Michels, Aaron;Russ, Holger A. A.
通讯作者：
Russ, Holger A. A.

Inherent Beta Cell Dysfunction Contributes to Autoimmune Susceptibility.