Chemoproteomic-Enabled Strategy to Study SLC Transporter Roles in Inflammation
研究 SLC 转运蛋白在炎症中的作用的化学蛋白质组学策略
基本信息
- 批准号:10298385
- 负责人:
- 金额:$ 17.24万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-07-01 至 2022-01-02
- 项目状态:已结题
- 来源:
- 关键词:Adaptive Immune SystemAddressAutoantibodiesAutoimmuneAutoimmune DiseasesB-LymphocytesBindingBiochemicalBiologyCCL21 geneCellsChemicalsClinicalCrohn&aposs diseaseDendritic CellsDetectionDevelopmentDiseaseDisease modelEnvironmental Risk FactorEvaluationEventFoundationsFunctional disorderFutureGene FamilyGeneticGenetic studyGoalsHematopoieticHomeostasisHumanImmuneImmune System DiseasesImmune responseImmunologyImpairmentInfectionInflammationInflammatoryInflammatory ResponseInnate Immune SystemInterferon Type IInterferonsInterventionInvadedInvestigationKnowledgeLeadLigandsLupusMass Spectrum AnalysisMediatingMembraneMetabolicMethodologyMolecularMusNucleic AcidsPathogenesisPathway interactionsPharmaceutical ChemistryPharmaceutical PreparationsPharmacologyPhysiologicalProcessProductionProteinsProteomicsReportingRoleSeriesSignal TransductionSignaling ProteinSiteSmall Inducible Cytokine A21StructureSuggestionSystemic Lupus ErythematosusTLR7 geneTNF geneTherapeuticToll-like receptorsVirus Diseasesautoimmune inflammationautoimmune pathogenesisbasechemoproteomicscytokinegenetic approachhuman diseaseimmunogenicimprovedin vivoin vivo Modelinhibitor/antagonistinnovationinsightloss of functionlysosomal proteinsmacrophagemembermouse modelnovelnovel strategiespathogenprotein functionprotein protein interactionsensorside effectsmall moleculesolutestemtherapeutic targettool
项目摘要
PROJECT SUMMARY
The innate immune system is the first line of defense against invading pathogens and intimately collaborates
with the adaptive immune system to maintain physiological homeostasis. However, components of the immune
response can sometimes become dysfunctional, failing in this protective role and even directly causing a variety
of autoimmune diseases. Immune dysfunction arises from an interplay of genetic and environmental factors,
however a mechanistic understanding of the various proteins and pathways that drive these conditions remains
incomplete. In particular, it is known that immune sensors, which are typically dedicated to protection against
infection, are sometimes usurped, and instead initiate and propagate autoimmune diseases such as systemic
lupus erythematosus (SLE) and Crohn’s disease. Specifically, self-induced signaling by nucleic acid-sensing
endosomal Toll-like receptors (TLRs 7 and 9) and the unchecked production of pro-inflammatory cytokines (e.g.
type I interferons; IFN-I) in plasmacytoid dendritic cells (pDCs) are key events in the pathogenesis of numerous
autoimmune conditions. Thus, compounds that can suppress the production of these cytokines in pDCs would
be clinically useful agents for the treatment of such diseases. Recently, loss-of-function studies of the poorly
characterized endolysosomal solute carrier gene family 15 member 4 (SLC15A4) in lupus mouse models
revealed significantly reduced disease manifestation as well as near complete suppression of TLR7/9-mediated
production of IFN-I and other proinflammatory cytokines. In this application, we have leveraged our lab’s
innovative chemoproteomic fragment-based ligand discovery platform to develop a suite of chemical probes that
engage SLC15A4 in human pDCs, block SLC15A4 mediated transport, and suppress IFN-I production in human
and mouse primary pDCs. We will utilize an interdisciplinary strategy that draws upon the fields of chemical
biology, immunology and mass spectrometry to illuminate how SLC15A4 controls TLR-mediated production of
IFN-I in primary human and mouse immune cells and evaluate pharmacological inhibition in vivo. Specifically,
we will investigate the effects of SLC15A4 pharmacological inhibition on endolysosomal homeostasis, on the
protein interaction network of SLC15A4 and on signaling in immune cells crucial to autoimmune pathophysiology.
Critically, we will assess the therapeutic potential of SLC15A4 in disease models of inflammation, such as lupus.
The chemical tools generated, and knowledge gained from these studies are certain to greatly advance our
understanding of SLC15A4 biology, enabling the identification of novel strategies to treat human autoimmune
diseases.
项目摘要
先天免疫系统是抵御入侵病原体的第一道防线,
与适应性免疫系统一起维持生理稳态。然而,免疫系统的组成部分
反应有时会变得功能失调,无法发挥这种保护作用,甚至直接导致各种
自身免疫性疾病免疫功能障碍由遗传和环境因素的相互作用引起,
然而,对驱动这些疾病的各种蛋白质和途径的机械理解仍然存在,
不完整特别地,已知免疫传感器,其通常专用于保护免受
感染,有时被篡夺,而是引发和传播自身免疫性疾病,
红斑狼疮(SLE)和克罗恩病。具体地说,通过核酸传感的自诱导信号传导
内体Toll样受体(TLR 7和9)和促炎细胞因子(例如,
浆细胞样树突状细胞(pDC)中的I型干扰素(IFN-1)是许多肿瘤发病机制中的关键事件,
自身免疫性疾病因此,可以抑制pDC中这些细胞因子的产生的化合物将
是治疗这些疾病的临床上有用的试剂。最近,对穷人的功能丧失研究
狼疮小鼠模型中的特征性内溶酶体溶质载体基因家族15成员4(SLC 15 A4)
显示出显著减少的疾病表现以及几乎完全抑制TLR 7/9介导的
IFN-1和其他促炎细胞因子的产生。在这个应用程序中,我们利用了我们实验室的
创新的基于化学蛋白质组学片段的配体发现平台,用于开发一套化学探针,
使SLC 15 A4参与人pDC,阻断SLC 15 A4介导的转运,并抑制人IFN-1的产生。
和小鼠原代pDC。我们将利用跨学科的战略,借鉴化学领域,
生物学、免疫学和质谱分析来阐明SLC 15 A4如何控制TLR介导的
IFN-I在原代人和小鼠免疫细胞中的表达,并评价体内药理学抑制。具体地说,
我们将研究SLC 15 A4药理学抑制对内溶酶体稳态的影响,
SLC 15 A4的蛋白质相互作用网络和对自身免疫病理生理学至关重要的免疫细胞中的信号传导。
重要的是,我们将评估SLC 15 A4在炎症疾病模型(如狼疮)中的治疗潜力。
从这些研究中产生的化学工具和获得的知识肯定会大大促进我们的研究。
了解SLC 15 A4生物学,从而能够确定治疗人类自身免疫性疾病的新策略
疾病
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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Christopher G Parker其他文献
Christopher G Parker的其他文献
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{{ truncateString('Christopher G Parker', 18)}}的其他基金
Chemoproteomic-Enabled Strategy to Study SLC Transporter Roles in Inflammation
研究 SLC 转运蛋白在炎症中的作用的化学蛋白质组学策略
- 批准号:
10434128 - 财政年份:2021
- 资助金额:
$ 17.24万 - 项目类别:
Chemoproteomic-Enabled Strategy to Study SLC Transporter Roles in Inflammation
研究 SLC 转运蛋白在炎症中的作用的化学蛋白质组学策略
- 批准号:
10686379 - 财政年份:2021
- 资助金额:
$ 17.24万 - 项目类别:
Chemoproteomic-Enabled Strategy to Study SLC Transporter Roles in Inflammation
研究 SLC 转运蛋白在炎症中的作用的化学蛋白质组学策略
- 批准号:
10597482 - 财政年份:2021
- 资助金额:
$ 17.24万 - 项目类别:
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