Mechanisms and Therapeutic Modulation of T Cell Autoimmune Responses in Sjogren's Syndrome
干燥综合征 T 细胞自身免疫反应的机制和治疗调节
基本信息
- 批准号:10214968
- 负责人:
- 金额:$ 53.15万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-04-10 至 2022-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAlternative TherapiesAmericanAttentionAttenuatedAutoimmune DiseasesAutoimmune ProcessAutoimmune ResponsesAutoimmunityAutologousBiological AssayBiological Response Modifier TherapyBiological Response ModifiersBiologyCellular ImmunologyCellular biologyChronicClinicalDevelopmentDiseaseDown-RegulationExocrine GlandsFunctional disorderFutureGalactose Binding LectinGalectin 3Gene ExpressionGoalsHealthHelper-Inducer T-LymphocyteHumanImmuneImmunologyImpairmentIn VitroInbred NOD MiceIndividualInflammationInflammatoryInjectionsInterferon Type IIInterleukin-10Interleukin-12Interleukin-17Interleukin-7KineticsKnockout MiceKnowledgeLacrimal gland structureLeadLentivirus VectorLigandsMediatingModelingMolecularMolecular BiologyMolecular ImmunologyMusOralOral healthOrganOutcomePathogenicityPathologyPathway interactionsPatientsProductionPropertyRegulatory T-LymphocyteReportingResearchResearch PersonnelResistanceSalivarySalivary GlandsSjogren&aposs SyndromeSystemT cell responseT-LymphocyteTestingTherapeuticXerostomiaautoreactivitybasechronic autoimmune diseasecytokineeffective therapyexpression vectoreye drynessfunctional disabilityimmunoregulationimprovedin vivoinnovationinsightmouse modelnovelnovel therapeuticstranscriptome sequencingtranscriptomics
项目摘要
Project Summary
Sjӧgren’s syndrome (SjS) is an autoimmune disease affecting the oral and systemic health of 4 million
Americans. Characterized by chronic inflammation and dysfunction of exocrine glands, SS causes dry mouth,
dry eyes and various systemic health problems, with no cure or effective biological therapy available. The
objective of this R01 project is to elucidate the negative impact of IL-7 and Th1 cytokines on Treg function in SjS
disease, and to test if enhancing TCF1 and Tim-3 in Tregs can improve and enhance their suppressor function,
resistance to IL-7/Th1 cytokines, and the ability to ameliorate SjS. Tregs in SjS-prone non-obese diabetic mice
are functionally impaired. Pro-inflammatory cytokines, including Th1 cytokines IFNγ and IL-12, can impair the
function and stability of Tregs to promote autoimmune inflammation. Our preliminary studies yielded important
evidence for the formation of our central hypothesis that IL-7 and Th1 cytokines contribute to aberrant Treg
function in SjS conditions, in part by downregulation of TCF1 and Tim-3, and that enhancing the
expression/activity of TCF1 and Tim-3 may improve and boost the immunosuppressive function, stability and
SjS-attenuating ability of these Tregs. In Aim 1, we will determine if forced expression of TCF1 in Tregs with
lentiviral gene expression vectors can improve/enhance their immunosuppressive function, stability under
inflammatory conditions, and ability to ameliorate SjS. In vitro Treg functional assays and in vivo Treg transfer
to SjS mouse model will be employed. In Aim 2, we will determine if enhancing Tim-3 activity or expression in
Tregs can improve and boost their immune-regulatory and SjS-attenuating function. We will enhance Tim-3
activation or expression using several approaches, including in vivo injection of Tim-3 ligand, in vitro stimulation
of Tregs with Tim-3 ligand, and force-expressing Tim-3 in Tregs using lentiviral vectors. We will test if enhancing
Tim-3 expression/activation can improve/boost the immunosuppressive function of normal and SjS-affected
mouse and human Tregs. In Aim 3, we will comprehensively define the transcriptomic changes in mouse and
human Tregs associated with SjS and induced by IL-7 and Th1 cytokines with high throughput NGS RNA-
sequencing, which will identify new molecular players and pathways underlying the defective Treg function in
SjS and induced by IL-7 and Th1 cytokines. Completion of this project will address a critical knowledge gap and
advance both basic understanding and translational modulation of Treg function and stability, which could lead
to development of Treg-based strategies for ameliorating SjS and various other autoimmune diseases in future.
Project Summary
Sjӧgren’s syndrome (SjS) is an autoimmune disease affecting the oral and systemic health of 4 million
Americans. Characterized by chronic inflammation and dysfunction of exocrine glands, SS causes dry mouth,
dry eyes and various systemic health problems, with no cure or effective biological therapy available. The
objective of this R01 project is to elucidate the negative impact of IL-7 and Th1 cytokines on Treg function in SjS
disease, and to test if enhancing TCF1 and Tim-3 in Tregs can improve and enhance their suppressor function,
resistance to IL-7/Th1 cytokines, and the ability to ameliorate SjS. Tregs in SjS-prone non-obese diabetic mice
are functionally impaired. Pro-inflammatory cytokines, including Th1 cytokines IFNγ and IL-12, can impair the
function and stability of Tregs to promote autoimmune inflammation. Our preliminary studies yielded important
evidence for the formation of our central hypothesis that IL-7 and Th1 cytokines contribute to aberrant Treg
function in SjS conditions, in part by downregulation of TCF1 and Tim-3, and that enhancing the
expression/activity of TCF1 and Tim-3 may improve and boost the immunosuppressive function, stability and
SjS-attenuating ability of these Tregs. In Aim 1, we will determine if forced expression of TCF1 in Tregs with
lentiviral gene expression vectors can improve/enhance their immunosuppressive function, stability under
inflammatory conditions, and ability to ameliorate SjS. In vitro Treg functional assays and in vivo Treg transfer
to SjS mouse model will be employed. In Aim 2, we will determine if enhancing Tim-3 activity or expression in
Tregs can improve and boost their immune-regulatory and SjS-attenuating function. We will enhance Tim-3
activation or expression using several approaches, including in vivo injection of Tim-3 ligand, in vitro stimulation
of Tregs with Tim-3 ligand, and force-expressing Tim-3 in Tregs using lentiviral vectors. We will test if enhancing
Tim-3 expression/activation can improve/boost the immunosuppressive function of normal and SjS-affected
mouse and human Tregs. In Aim 3, we will comprehensively define the transcriptomic changes in mouse and
human Tregs associated with SjS and induced by IL-7 and Th1 cytokines with high throughput NGS RNA-
sequencing, which will identify new molecular players and pathways underlying the defective Treg function in
SjS and induced by IL-7 and Th1 cytokines. Completion of this project will address a critical knowledge gap and
advance both basic understanding and translational modulation of Treg function and stability, which could lead
to development of Treg-based strategies for ameliorating SjS and various other autoimmune diseases in future.
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Secretome Analysis of Inductive Signals for BM-MSC Transdifferentiation into Salivary Gland Progenitors.
- DOI:10.3390/ijms21239055
- 发表时间:2020-11-28
- 期刊:
- 影响因子:5.6
- 作者:Mona M;Kobeissy F;Park YJ;Miller R;Saleh W;Koh J;Yoo MJ;Chen S;Cha S
- 通讯作者:Cha S
Inhibition of breast cancer resistance protein (ABCG2) in human myeloid dendritic cells induces potent tolerogenic functions during LPS stimulation.
- DOI:10.1371/journal.pone.0104753
- 发表时间:2014
- 期刊:
- 影响因子:3.7
- 作者:Jin JO;Zhang W;Wong KW;Kwak M;van Driel IR;Yu Q
- 通讯作者:Yu Q
Clinical usefulness of anti-muscarinic type 3 receptor autoantibodies in patients with primary Sjögren's syndrome.
- DOI:10.55563/clinexprheumatol/gy6udz
- 发表时间:2021-07
- 期刊:
- 影响因子:3.7
- 作者:Mona M;Mondello S;Hyon JY;Saleh W;Han K;Lee HJ;Ha YJ;Kang EH;Lee YJ;Cha S
- 通讯作者:Cha S
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SEUNGHEE CHA其他文献
SEUNGHEE CHA的其他文献
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{{ truncateString('SEUNGHEE CHA', 18)}}的其他基金
PKR sensing of mitochondrial dsRNA in childhood Sjogrens disease
儿童干燥病线粒体 dsRNA 的 PKR 传感
- 批准号:
10637496 - 财政年份:2023
- 资助金额:
$ 53.15万 - 项目类别:
Cytoplasmic mitochondrial dsRNA in pediatric Sjogren's syndrome
小儿干燥综合征中的细胞质线粒体 dsRNA
- 批准号:
10287866 - 财政年份:2021
- 资助金额:
$ 53.15万 - 项目类别:
Expression and function of microRNA in autoimmune Sjogren's Syndrome
microRNA在自身免疫性干燥综合征中的表达和功能
- 批准号:
8668761 - 财政年份:2010
- 资助金额:
$ 53.15万 - 项目类别:
Expression and function of microRNA in autoimmune Sjogren's Syndrome
microRNA在自身免疫性干燥综合征中的表达和功能
- 批准号:
8100296 - 财政年份:2010
- 资助金额:
$ 53.15万 - 项目类别:
Expression and function of microRNA in autoimmune Sjogren's Syndrome
microRNA在自身免疫性干燥综合征中的表达和功能
- 批准号:
8475578 - 财政年份:2010
- 资助金额:
$ 53.15万 - 项目类别:
Expression and function of microRNA in autoimmune Sjogren's Syndrome
microRNA在自身免疫性干燥综合征中的表达和功能
- 批准号:
8272468 - 财政年份:2010
- 资助金额:
$ 53.15万 - 项目类别:
Defective Saliva Secretion in Autoimmune NOD mice
自身免疫性 NOD 小鼠唾液分泌缺陷
- 批准号:
7210886 - 财政年份:2007
- 资助金额:
$ 53.15万 - 项目类别:
Defective Saliva Secretion in Autoimmune NOD mice
自身免疫性 NOD 小鼠唾液分泌缺陷
- 批准号:
7473288 - 财政年份:2007
- 资助金额:
$ 53.15万 - 项目类别:
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