Role of PTPN2 in rheumatoid arthritis

PTPN2在类风湿性关节炎中的作用

基本信息

批准号：
10155408
负责人：
Nunzio Bottini
金额：
$ 52.63万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10155408
关键词：
Adolescent Affect Applications Grants Arthritis Arthritogenic Autoimmune Diseases Autoimmunity CD4 Positive T Lymphocytes Cells Colon Complex Cytokine Receptors Data Development Disease Equilibrium FOXP3 gene Funding Genes Genetic Genetic Risk Goals Grant Heterozygote Homozygote Human Immune Immunology In Vitro Inflammation Inflammatory Bowel Diseases Interleukin-17 Interleukin-6 Intestines Investigation Janus kinase Joints Knock-out Knowledge Lead Light Modeling Morbidity - disease rate Mus Myeloid Cells Orphan Pathogenesis Pathogenicity Patients Peripheral Phase Phenotype Phosphorylation Physiology Population Process Protein Dephosphorylation Receptor Signaling Regulatory T-Lymphocyte Research Rheumatoid Arthritis Risk Role STAT protein STAT3 gene Severities Signal Pathway Signal Transduction Source T-Cell Receptor T-cell protein tyrosine phosphatase Testing Tissues Variant arthritis therapy autoimmune arthritis base cytokine genetic manipulation genetic variant human disease in vivo loss of function mouse model novel overexpression personalized medicine receptor risk variant src-Family Kinases

项目摘要

ABSTRACT The objective of this grant application is to understand how loss-of-function genetic variants of the PTPN2 gene -encoding the T cell-protein tyrosine phosphatase (TC-PTP)- enhance risk of rheumatoid arthritis (RA). PTPN2 is ubiquitous, and very highly expressed in immune cells and is a critical negative regulator of Janus kinases and signal transducers and activators of transcription downstream multiple cytokine receptors. In order to model the mechanism of action of PTPN2 autoimmunity-associated variants in RA, we assessed mice carrying Ptpn2 haploinsufficiency (Ptpn2+/- mice), which causes a loss of expression of PTPN2 comparable to the human PTPN2 RA-risk variants. We found that in the SKG RA model- characterized by CD4 T cell-driven disease- partial loss of function of PTPN2 caused significant enhancement of arthritis severity. By leveraging conditional Ptpn2 haploinsufficiency and fate-mapping mice, we showed that the phenotype of SKG.Ptpn2+/- mice is due to enhanced inflammation-induced FoxP3+ regulatory T cell (Treg) instability, a process known to lead to conversion of peripheral FoxP3+ Treg into pathogenic FoxP3- “exTreg” expressing interleukin-17 (IL-17). We have evidence that the enhanced conversion of Ptpn2+/- Tregs into IL-17-producing “exTreg” is due to increased STAT3 phosphorylation after stimulation with IL-6 and potentially other inflammation-induced factors. Here we apply for funding to further understand the mechanism of action of PTPN2 in Treg instability and the pathogenesis of RA via mouse immunology and cell signaling studies. In Aim 1 and 2 we will elucidate the mechanism and topology of enhanced inflammation-induced instability and pathogenicity of SKG.Ptpn2+/- Treg. In Aim 3 we will assess whether overexpression of PTPN2 in Treg can reverse the Treg and arthritis phenotype induced by Ptpn2+/- in SKG mice. Our long-term goal is to acquire knowledge of PTPN2 functional genetics to enable the discovery of personalized and non-immunosuppressive therapies for RA patients carrying genetic PTPN2 risk variants.

抽象的该赠款应用的目的是了解PTPN2基因2基因的损失功能遗传学 - 编码酪氨酸酪氨酸磷酸酶（TC -PTP） - 源自炎的风险（RA）无处不在，在免疫细胞中非常高度表达，如Januses激酶的批判性调节剂和转录下游细胞因子细胞因子受体转录的信号传感器和激活因子。 PTPN2自身免疫相关变体的作用机理，我们评估了携带PTPN2的小鼠单倍不足（PTPN2 +/-小鼠），这会导致PTPN2表达与人PTPN2的表达丧失 RA风险的变体。 PTPN2的功能通过利用有条件的PTPN2引起关节炎的严重程度。单倍不足和命运型小鼠增强的炎症引起的FOXP3+常规T细胞（Treg）不稳定性，已知会导致转化表达白介素17（IL-17）的致病性foxp3-“ foxp3-” PTPN2 +/- tregs IL-17产生的“ fexreg”的转化增强是由于STAT3增加 IL-6和其他炎症诱导的因子刺激后的磷酸化。资金以进一步了解Treg不稳定性和RA发病机理的PTPN2机制通过小鼠免疫学和细胞信号研究，我们将阐明机制和拓扑 SKG的炎症 - 诱导性和致病性。 Treg中PTPN2的过表达是否可以逆转由PTPN2 +/-诱导的Treg和Artype SKG小鼠。我们的长期目标是获取PTPN2功能遗传学的知识针对携带遗传PTPN2风险变异的RA患者的个性化和非注射疗法。