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Determinants of follicular helper T cell expansion in lupus

狼疮滤泡辅助 T 细胞扩张的决定因素

基本信息

批准号：
10679012
负责人：
Laurence Morel
金额：
$ 64.04万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10679012
关键词：
Affect Affinity Autoantibodies Automobile Driving B-Lymphocyte Subsets B-Lymphocytes BLR1 gene C57BL/6 Mouse CD4 Positive T Lymphocytes Cell Differentiation process Cell physiology Cells Congenic Mice Cues Data Diet Disease Disease Outcome Drug or chemical Tissue Distribution Environmental Impact Environmental Risk Factor Exhibits Frequencies Genes Genetic Genetic Determinism Genome Germ-Free Glucose Glutamine Glycolysis Inhibition Health Helper-Inducer T-Lymphocyte Human ITGAX gene Immunoglobulin A Immunoglobulin Class Switching Investigation Knowledge Lupus Metabolic Metabolic Pathway Metabolism Modeling Molecular Mus Norleucine Outcome Pathway interactions Patients Peripheral Production Reagent SLEB1 gene SLEB3 gene Severities Severity of illness Sorting Spleen Susceptibility Gene Systemic Lupus Erythematosus T-Lymphocyte Subsets Testing Therapeutic Tryptophan Tryptophan Metabolism Pathway Validation Variant autoreactivity cohort congenic dietary manipulation experimental study fecal microbiota follow-up genetic signature gut dysbiosis gut microbiota improved in vitro Assay in vivo innovation interleukin-21 lupus prone mice metabolome metabolomics microbial microbiome mouse model novel pathogenic autoantibodies programmed cell death protein 1 response solute synergism transcriptome transcriptome sequencing transcriptomics

项目摘要

Project Summary/Abstract The expansion of follicular helper (Tfh) cells and related subpopulations is correlated with the severity of human lupus disease and is shared by all lupus-prone mouse models. However, the mechanisms for the expansion of Tfh cells in lupus are largely unknown. Thus, the objective of this proposal is to shed new light on the mechanisms that are responsible for Tfh cell expansion in lupus using innovative cellular and molecular approaches based on the obtained data from the B6.Sle1.Sle2.Sle3 triple congenic (TC) murine model of lupus. Accordingly, we have identified genetic, as well as microbial and metabolic determinants that modulate lupus Tfh cell expansion. Transferring the perturbed gut microbiota of lupus mice into mouse host crucially contributed to Tfh cell expansion. Additionally, an altered tryptophan (Trp) metabolism also enhanced Tfh cell expansion, which was reduced by manipulating dietary Trp levels in mice. Finally, inhibiting glycolysis with 2-deoxi-D-glucose (2DG), or glutaminolysis with 6-Diazo-5-oxo-L-norleucine (DON) functionally diminished lupus Tfh cell differentiation. Our hypothesis is that the expansion of Tfh cells implicated in lupus integrates cues from susceptibility genes, dysregulated microbiome and environmental metabolites. In support of this hypothesis, our data demonstrate that TC Tfh cells possess a novel metabolic gene signature, potentially driving the autoreactive Tfh cell expansion directed by a unique metabolic flux. Thus, we propose combining the analyses of Tfh cell transcriptome and metabolome in response to variations of the aforementioned cues as a means to elucidate the involved molecular mechanisms, singly or in combination, impacting the fate of Tfh cells in lupus. We also propose to investigate the effects of genetic and environmental determinants functionally affecting Tfh cells on two B cell subsets, CD11c+Tbet+ B cells (ABCs) and IgA+ B cells. To proceed, the following Specific Aims are proposed. 1. To explore the mechanisms by which lupus susceptibility genes modulate the Tfh cell transcriptome and metabolome in the two unrelated TC and (NZW x BXSB.Yaa)F1 lupus models. 2. To identify the impact of environmental factors on the Tfh transcriptome and metabolome in TC mice. And 3. To elucidate the molecular mechanisms implicated in the expansion of Tfh cells in lupus patients. Obtained results from these mechanistic experiments will be the first in-depth investigation of Tfh cell expansion directed by environmental and genetic determinants, which may be reprogrammed for a sustainable therapeutic strategy to perhaps improve lupus patients' health.

项目摘要/摘要滤泡辅助细胞(TFH)及相关亚群的扩张与人类疾病的严重程度相关狼疮性疾病，所有狼疮易感小鼠模型都有这种现象。然而，扩大的机制，狼疮中的TFH细胞在很大程度上是未知的。因此，这项提案的目标是对这些机制作出新的解释。使用创新的细胞和分子方法在狼疮中负责TFH细胞的扩张根据B6.Sle1.Sle2.Sle3三基因同源(TC)狼疮小鼠模型所获得的数据。因此，我们已经确定了调节狼疮Tfh细胞扩张的遗传、微生物和代谢决定因素。将狼疮小鼠扰动的肠道微生物区系转移到小鼠宿主体内对TFH细胞的形成至关重要扩张。此外，色氨酸(Trp)代谢的改变也促进了TFH细胞的扩张，这是通过控制小鼠饮食中的色氨酸水平来降低。2-脱氧-D-葡萄糖(2DG)抑制糖酵解， 6-重氮-5-氧代-L去亮氨酸(DON)对狼疮Tfh细胞分化的抑制作用。我们的假设是，与狼疮有关的TFH细胞的扩张整合了易感基因的线索，微生物群和环境代谢物的失调。为了支持这一假设，我们的数据表明 TC Tfh细胞具有新的代谢基因信号，潜在地驱动自身反应性Tfh细胞的扩张由一种独特的新陈代谢流引导。因此，我们建议将TFH细胞转录组的分析与代谢组对上述信号变化的反应作为阐明相关分子的一种手段影响狼疮中TFH细胞命运的单独或联合机制。我们还提议调查影响Tfh细胞功能的遗传和环境决定因素对两个B细胞亚群的影响， CD11c+T细胞(ABCs)和IgA+B细胞。为此，提出了以下具体目标。1.至探讨狼疮易感基因调控TFH细胞转录组和两个无关的TC和(NZW x BXSB.Yaa)F1狼疮模型中的代谢组。2.确定环境因素对TC小鼠转铁蛋白转录组和代谢组的影响。3.阐明分子狼疮患者TFH细胞增殖机制的研究。从这些机械论中获得的结果实验将是第一次深入研究环境和遗传指导下的TFH细胞扩增决定因素，可能被重新编程为可持续的治疗策略，可能会改善狼疮病人的健康。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Dissociation and flow cytometric isolation of murine intestinal epithelial cells for multi-omic profiling.

DOI：
10.1016/j.xpro.2022.101936
发表时间：
2023-03-17
期刊：
STAR PROTOCOLS
影响因子：
0
作者：
Ge, Yong;Zadeh, Mojgan;Mohamadzadeh, Mansour
通讯作者：
Mohamadzadeh, Mansour

Pharmacologic inhibition of glycolysis prevents the development of lupus by altering the gut microbiome in mice.

DOI：
10.1016/j.isci.2023.107122
发表时间：
2023-07-21
期刊：
ISCIENCE
影响因子：
5.8
作者：
Elshikha, Ahmed S.;Ge, Yong;Brown, Josephine;Kanda, Nathalie;Zadeh, Mojgan;Abboud, Georges;Choi, Seung-Chul;Silverman, Gregg;Garrett, Timothy J.;Clapp, William L.;Mohamadzadeh, Mansour;Morel, Laurence
通讯作者：
Morel, Laurence

Vitamin B12 and gut-brain homeostasis in the pathophysiology of ischemic stroke.