Bidirectional paracrine signaling in the establishment of invasive aspergillosis
侵袭性曲霉病建立中的双向旁分泌信号传导
基本信息
- 批准号:10574521
- 负责人:
- 金额:$ 47.2万
- 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:2021-03-01 至 2026-02-28
- 项目状态:未结题
- 来源:
- 关键词:AddressAffectAntifungal AgentsAspergillosisAspergillusAspergillus fumigatusAutomobile DrivingBiochemicalBiological AssayCalciumCommunicationDataDevelopmentDiseaseDisease ProgressionEquilibriumFamilyFilamentFoundationsFutureG-Protein-Coupled ReceptorsGene FusionGenesGenetic TranscriptionGoalsGrowthHost DefenseImmune responseImmunocompromised HostIn VitroIntegration Host FactorsKineticsKnowledgeLanguageLeukocytesLigandsLipidsMacrophageMediatingModelingMolecularMusMycosesOpticsOxygenasesParacrine CommunicationPathway interactionsPatientsPatternPenetrationPhagocytesPharmacologic SubstancePositioning AttributePredispositionProcessProstaglandin-Endoperoxide SynthaseRegulationReporterReporter GenesRoleSeriesSeveritiesSignal PathwaySignal TransductionSystemTestingTherapeuticTherapeutic InterventionTissuesVirulenceVisualWith lateralityWorkZebrafishanalogantagonistdefense responsedesignfungushuman diseaseimprovedin vivoinsightmicrodevicemigrationmortalitymouse modelmutantneutrophilnovel strategiespathogenreceptorresponsesmall moleculesmall molecule inhibitortargeted treatmenttranscription factortranscriptometranscriptome sequencing
项目摘要
ABSTRACT
Invasive aspergillosis (IA) caused by Aspergillus fumigatus is characterized by uncontrolled filamentous hyphal
growth deep into host tissues and is a fatal disease of immunocompromised patients with mortality rates as high
as 90%. This high mortality rate indicates the critical need for improved antifungal therapeutic strategies. We
have uncovered a bidirectional lipid signaling system between the fungus and host that mediates invasive hyphal
growth and phagocyte activation. Based on strong preliminary data, this communication system consists of
structurally similar fungal and host ligands (e.g. oxylipins) that are recognized by specific fungal and host G
protein coupled receptors (GPCRs). The fungal and host oxylipins work in opposition to regulate fungal growth
and leukocyte functionality. We hypothesize that fungal and host oxylipins are cross-Kingdom molecular analogs
that signal through specific GPCR cascades, inducing penetrating hyphal growth and manipulating host defense
responses to drive IA progression. Our data not only provide new insight into how eukaryotic pathogens and
their hosts communicate with one another directly during disease but also provide a new foundation for
experimental approaches to decipher, manipulate, and control this communication system in favor of the host.
Accordingly, we will (1) Identify the oxylipins and their transcriptional cascades that regulate invasive
branching growth and (2) Characterize the receptors by which fungus and host recognize each other’s
oxylipins and the consequences of this recognition. GPCR are particularly propitious targets for therapeutic
design (40% of current pharmaceuticals target GPCR). Thus, upon completion of this work, we anticipate that
we will have delineated a new fungal-host ligand-receptor communication language amenable to therapeutic
intervention to inhibit filamentous invasive growth during human disease.
抽象的
由烟曲霉引起的侵袭性曲霉菌病 (IA) 的特点是不受控制的丝状菌丝
生长深入宿主组织,是免疫功能低下患者的致命疾病,死亡率很高
为 90%。这种高死亡率表明迫切需要改进抗真菌治疗策略。我们
发现了真菌和宿主之间介导侵入性菌丝的双向脂质信号系统
生长和吞噬细胞激活。基于强有力的初步数据,该通信系统包括
结构相似的真菌和宿主配体(例如氧脂素),可被特定真菌和宿主 G 识别
蛋白质偶联受体(GPCR)。真菌和宿主氧脂素相反地调节真菌生长
和白细胞功能。我们假设真菌和宿主氧脂质是跨界分子类似物
通过特定的 GPCR 级联发出信号,诱导穿透性菌丝生长并操纵宿主防御
驱动 IA 进展的反应。我们的数据不仅提供了关于真核病原体如何
它们的宿主在疾病期间直接相互交流,但也为
破译、操纵和控制该通信系统以有利于宿主的实验方法。
因此,我们将 (1) 鉴定调节侵入性的氧脂质及其转录级联反应。
分支生长和(2)表征真菌和宿主相互识别的受体
氧脂质以及这种认识的后果。 GPCR 是特别有利的治疗靶点
设计(目前 40% 的药物以 GPCR 为目标)。因此,在完成这项工作后,我们预计
我们将描绘出一种新的真菌-宿主配体-受体通讯语言,适合治疗
在人类疾病期间抑制丝状侵入性生长的干预措施。
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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NANCY P KELLER其他文献
NANCY P KELLER的其他文献
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{{ truncateString('NANCY P KELLER', 18)}}的其他基金
A Universal Fungal Transposase System for Increasing Natural Product and Protein Titers
用于提高天然产物和蛋白质滴度的通用真菌转座酶系统
- 批准号:
10760459 - 财政年份:2023
- 资助金额:
$ 47.2万 - 项目类别:
Cryptosporidium's polyketide secondary metabolite: exogenous production, compound characterization and function in intracellular development.
隐孢子虫的聚酮化合物次生代谢物:外源产生、化合物表征和细胞内发育中的功能。
- 批准号:
10657338 - 财政年份:2022
- 资助金额:
$ 47.2万 - 项目类别:
Cryptosporidium's polyketide secondary metabolite: exogenous production, compound characterization and function in intracellular development.
隐孢子虫的聚酮化合物次级代谢产物:外源产生、化合物表征和细胞内发育中的功能。
- 批准号:
10354414 - 财政年份:2022
- 资助金额:
$ 47.2万 - 项目类别:
Bidirectional paracrine signaling in the establishment of invasive aspergillosis
侵袭性曲霉病建立中的双向旁分泌信号传导
- 批准号:
10359102 - 财政年份:2021
- 资助金额:
$ 47.2万 - 项目类别:
Comprehensive analysis of NRPS-derived metabolomes of three Aspergillus species
三种曲霉属 NRPS 衍生代谢组的综合分析
- 批准号:
8798807 - 财政年份:2014
- 资助金额:
$ 47.2万 - 项目类别:
Accessing the hidden biosynthetic capabilities of fungi
获取真菌隐藏的生物合成能力
- 批准号:
10188555 - 财政年份:2014
- 资助金额:
$ 47.2万 - 项目类别:
Accessing the hidden biosynthetic capabilities of fungi
获取真菌隐藏的生物合成能力
- 批准号:
10728368 - 财政年份:2014
- 资助金额:
$ 47.2万 - 项目类别:
Accessing the hidden biosynthetic capabilities of fungi
获取真菌隐藏的生物合成能力
- 批准号:
10379404 - 财政年份:2014
- 资助金额:
$ 47.2万 - 项目类别:
Comprehensive analysis of NRPS-derived metabolomes of three Aspergillus species
三种曲霉属 NRPS 衍生代谢组的综合分析
- 批准号:
8986191 - 财政年份:2014
- 资助金额:
$ 47.2万 - 项目类别:
Accessing the hidden biosynthetic capabilities of fungi
获取真菌隐藏的生物合成能力
- 批准号:
10608978 - 财政年份:2014
- 资助金额:
$ 47.2万 - 项目类别:
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