Biochemical and functional characterization of a novel anti-inflammatory biogenic amine
新型抗炎生物胺的生化和功能表征
基本信息
- 批准号:10610183
- 负责人:
- 金额:$ 73.73万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-07-06 至 2028-06-30
- 项目状态:未结题
- 来源:
- 关键词:Adenylate CyclaseAminesAnimal ModelAnti-Inflammatory AgentsAntigen-Presenting CellsAntiinflammatory EffectAutoimmune DiseasesBindingBiochemicalBiogenic AminesBiologicalBiological AssayBiological Response ModifiersBiophysicsBiotinylationCD8-Positive T-LymphocytesCRISPR libraryCatabolismCell secretionCellsClinicalComplexCyclic AMPDataDendritic CellsDiseaseDrug KineticsEndowmentEnzymesErythemaEssential Amino AcidsExhibitsExperimental ModelsForskolinG-Protein-Coupled ReceptorsGenerationsGeneticGenetic TranscriptionGlomerulonephritisGoalsHumanIL17 geneImmuneImmune ToleranceImmunologicsImmunophenotypingImmunoprecipitationImmunosuppressionIn VitroIncubatedInflammatoryInterferon Type IIInterleukin-1 betaInterleukin-6KnowledgeKynurenineLateralLibrariesLigandsLupusLymphatic Endothelial CellsMammalian CellMapsMass Spectrum AnalysisMediatingMelatoninMemoryMetabolic PathwayModelingMusNephritisNuclearNuclear TranslocationOrphanPathologicPathway interactionsPharmaceutical PreparationsPharmacodynamicsPhenotypePhosphotransferasesPhysiologicalProcessProductionProteinuriaPsoriasisRegulationReportingSTAT1 geneSeriesSerotoninSerumSignal TransductionSignal Transduction PathwaySkinStimulusSystemic Lupus ErythematosusT memory cellT-Cell ActivationTNF geneTestingTherapeuticThickTitrationsToxic effectTryptophanTryptophan Metabolism PathwayUrea Nitrogenadaptive immune responseanalogbiophysical analysischemokinecytokineexperimental studyimmunoregulationimprovedin vitro testingin vivokidney dysfunctionknock-downmouse modelnephrotoxicitynovelphosphoproteomicsprotective effectreceptorscreeningstem
项目摘要
Summary
Tryptophan (Trp) catabolism is a complex pathway that generates over fifty metabolites in a cell-specific manner.
Besides being the precursor of serotonin and melatonin, tryptophan generates a cascade of metabolites known
as kynurenines. Kynurenine metabolites are regarded as one of the most powerful mediators of immune
regulation. The thrust of this application stems from our original observations that: (i) lymphatic endothelial cells
(LEC) and dendritic cells (DCs) secrete a previously unidentified biogenic amine, 3HKA, which derives from a
lateral pathway of Trp catabolism, whose function is currently unknown; (ii) 3HKA exhibits a clear anti-
inflammatory profile by inhibiting the STAT1/NF-κΒ pathway in both mouse and human dendritic cells (DCs) with
a consequent decrease in the release of pro-inflammatory chemokines and cytokines; most notably, IL-6,
IL12p70 and TNFα; (iii) in vivo, 3HKA exerts protective effects in the experimental model of psoriasis by
decreasing skin thickness, erythema, scaling and fissuring. In a model of nephrotoxic lupus, 3HKA improved
proteinuria and serum urea nitrogen, overall ameliorating the immune-mediated glomerulonephritis and renal
dysfunction. As such, the ultimate goal of this application is to fully characterize the biological activity of 3HKA.
In Aim 1, a series of biochemical and biophysical analyses will be employed to identify the enzyme responsible
for 3HKA production and investigate the regulation of its synthesis under physiological and pathological
conditions. In Aim 2, by using biotinylated derivatives of 3HKA, and a series of biochemical and biophysical
experiments, we will identify the receptor target of 3HKA and its expression profile. In Aim 3, using targeted and
untargeted phosphoproteomic approaches, screening of kinase libraries and CRISPR/Cas9 knock down
strategies we will characterize the 3HKA signal transduction pathway. Additionally, we will analyze the effect of
3HKA on T cell activation and differentiation into a TH1, TH2, TH17 phenotype, naïve vs effector and memory T
cell transition and 3HKA effect on maturation/activation of different APC (DC, pDC, MΦ). Immunophenotyping
will be performed both in vitro and in vivo, using psoriasis or nephrotoxic lupus as animal models. Finally, in Aim
4 we leveraged our knowledge on 3HKA and generated 3HKA-like compounds, predicted to have an anti-
inflammatory effect. These analogs will be screened in a series of in vitro and in vivo assay to fully assess their
potential as novel immunomodulatory molecules
概括
色氨酸 (Trp) 分解代谢是一条复杂的途径,以细胞特异性方式产生 50 多种代谢物。
除了是血清素和褪黑激素的前体之外,色氨酸还会产生一系列已知的代谢物
犬尿氨酸代谢物被认为是最强大的免疫介质之一。
该应用的主旨源于我们最初的观察:(i)淋巴内皮细胞。
(LEC) 和树突状细胞 (DC) 分泌一种先前未鉴定的生物胺 3HKA,它源自
(ii) 3HKA 表现出明显的抗
通过抑制小鼠和人类树突状细胞 (DC) 中的 STAT1/NF-κB 通路来调节炎症特征
促炎趋化因子和细胞因子的释放随之减少;最显着的是 IL-6,
IL12p70 和 TNFα;(iii) 在体内,3HKA 通过以下方式在银屑病实验模型中发挥保护作用:
在肾毒性狼疮模型中,3HKA 的皮肤厚度、红斑、鳞屑和裂痕有所改善。
蛋白尿和血清尿素氮,总体改善免疫介导的肾小球肾炎和肾病
因此,该应用的最终目标是充分表征 3HKA 的生物活性。
在目标 1 中,将采用一系列生化和生物物理分析来鉴定负责的酶。
3HKA的产生并研究其合成在生理和病理条件下的调控
在目标2中,通过使用3HKA的生物素化衍生物,以及一系列的生物化学和生物物理。
实验中,我们将使用靶向和鉴定 3HKA 的受体靶标及其表达谱。
非靶向磷酸化蛋白质组学方法、激酶文库筛选和 CRISPR/Cas9 敲低
我们将描述 3HKA 信号转导途径的策略此外,我们将分析其效果。
3HKA 关于 T 细胞激活和分化为 TH1、TH2、TH17 表型、幼稚 T 细胞与效应细胞和记忆 T 细胞的关系
细胞转变和 3HKA 对不同 APC(DC、pDC、MΦ)成熟/激活的影响。
将使用银屑病或肾毒性狼疮作为动物模型进行体外和体内实验。
4 我们利用我们对 3HKA 的了解,生成了类似 3HKA 的化合物,预计具有抗-
这些类似物将在一系列体外和体内试验中进行筛选,以充分评估它们的效果。
作为新型免疫调节分子的潜力
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)
专利数量(0)
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LAURA SANTAMBROGIO其他文献
LAURA SANTAMBROGIO的其他文献
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{{ truncateString('LAURA SANTAMBROGIO', 18)}}的其他基金
Radiation Effect on Immune Cells and the Microbiome
辐射对免疫细胞和微生物组的影响
- 批准号:
10517808 - 财政年份:2022
- 资助金额:
$ 73.73万 - 项目类别:
Radiation Effect on Immune Cells and the Microbiome
辐射对免疫细胞和微生物组的影响
- 批准号:
10708066 - 财政年份:2022
- 资助金额:
$ 73.73万 - 项目类别:
Effects of Glycation and Carbonylation on MHC II-restricted immunity
糖化和羰基化对 MHC II 限制性免疫的影响
- 批准号:
10335198 - 财政年份:2020
- 资助金额:
$ 73.73万 - 项目类别:
Effects of Glycation and Carbonylation on MHC II-restricted immunity
糖化和羰基化对 MHC II 限制性免疫的影响
- 批准号:
10548190 - 财政年份:2020
- 资助金额:
$ 73.73万 - 项目类别:
Effects of Glycation and Carbonylation on MHC II-restricted immunity
糖化和羰基化对 MHC II 限制性免疫的影响
- 批准号:
9974042 - 财政年份:2020
- 资助金额:
$ 73.73万 - 项目类别:
DYNAMICS AND TUNING OF THE MHC II PRESENTED PEPTIDOME
MHC II 呈递肽段的动力学和调节
- 批准号:
10016167 - 财政年份:2018
- 资助金额:
$ 73.73万 - 项目类别:
DYNAMICS AND TUNING OF THE MHC II PRESENTED PEPTIDOME
MHC II 呈递肽段的动力学和调节
- 批准号:
10468682 - 财政年份:2018
- 资助金额:
$ 73.73万 - 项目类别:
MHC class II-restricted immune response in immunosenescence
免疫衰老中 MHC II 类限制性免疫反应
- 批准号:
9141793 - 财政年份:2014
- 资助金额:
$ 73.73万 - 项目类别:
MHC class II-restricted immune response in immunosenescence
免疫衰老中 MHC II 类限制性免疫反应
- 批准号:
9065462 - 财政年份:2014
- 资助金额:
$ 73.73万 - 项目类别:
MHC class II-restricted immune response in immunosenescence
免疫衰老中 MHC II 类限制性免疫反应
- 批准号:
9269951 - 财政年份:2014
- 资助金额:
$ 73.73万 - 项目类别:
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