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:10359102
- 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 FactorsKineticsKnowledgeLanguageLateralLeadLeukocytesLigandsLipidsMediatingModelingMolecularMusMycosesOpticsOxygenasesParacrine CommunicationPathway interactionsPatientsPatternPhagocytesPharmacologic SubstancePositioning AttributeProcessProstaglandin-Endoperoxide SynthaseRegulationReporterReporter GenesRoleSeriesSeveritiesSignal PathwaySignal TransductionSystemTestingTherapeuticTherapeutic InterventionTissuesVirulenceVisualWorkZebrafishanalogantagonistbasedata communicationdefense responsedesignfungushuman diseaseimprovedin vivoinsightmacrophagemicrodevicemigrationmortalitymouse 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.
摘要
由烟曲霉菌引起的侵袭性曲霉病(IA)的特征是丝状菌丝不受控制
生长到宿主组织深处,是免疫低下患者的一种致命疾病,死亡率高达
高达90%。如此高的死亡率表明迫切需要改进抗真菌治疗策略。我们
已经发现了真菌和宿主之间的双向脂质信号系统,该系统介导了入侵菌丝
生长和吞噬细胞的激活。基于强大的初步数据,这一通信系统由以下部分组成
由特定真菌和宿主G识别的结构相似的真菌和宿主配体(例如氧脂)
蛋白偶联受体(GPCRs)。真菌和宿主氧脂相反地作用于调节真菌的生长。
和白细胞功能。我们假设真菌和宿主氧磷脂是跨王国的分子类似物
该信号通过特定的GPCR级联反应,诱导穿透性菌丝生长和操纵宿主防御
推动IA进展的反应。我们的数据不仅提供了对真核病原体和
它们的宿主在疾病期间直接相互交流,但也为
破译、操纵和控制这种有利于主机的通信系统的实验方法。
因此,我们将(1)确定氧合脂及其调节侵袭性的转录级联
分枝生长和(2)真菌和寄主相互识别的受体的特征
氧磷脂和这种认识的后果。Gpr是特别有利的治疗靶点。
设计(目前40%的药物以GPCR为靶点)。因此,在这项工作完成后,我们预计
我们将描绘出一种新的真菌-宿主配体-受体沟通语言
在人类疾病期间抑制丝状菌侵袭性生长的干预。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
NANCY P KELLER其他文献
NANCY P KELLER的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
10574521 - 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:
相似海外基金
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
- 批准号:
BB/Z514391/1 - 财政年份:2024
- 资助金额:
$ 47.2万 - 项目类别:
Training Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
- 批准号:
2312555 - 财政年份:2024
- 资助金额:
$ 47.2万 - 项目类别:
Standard Grant
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
- 批准号:
2327346 - 财政年份:2024
- 资助金额:
$ 47.2万 - 项目类别:
Standard Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
- 批准号:
ES/Z502595/1 - 财政年份:2024
- 资助金额:
$ 47.2万 - 项目类别:
Fellowship
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
- 批准号:
ES/Z000149/1 - 财政年份:2024
- 资助金额:
$ 47.2万 - 项目类别:
Research Grant
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
- 批准号:
23K24936 - 财政年份:2024
- 资助金额:
$ 47.2万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
- 批准号:
2901648 - 财政年份:2024
- 资助金额:
$ 47.2万 - 项目类别:
Studentship
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
- 批准号:
488039 - 财政年份:2023
- 资助金额:
$ 47.2万 - 项目类别:
Operating Grants
New Tendencies of French Film Theory: Representation, Body, Affect
法国电影理论新动向:再现、身体、情感
- 批准号:
23K00129 - 财政年份:2023
- 资助金额:
$ 47.2万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
The Protruding Void: Mystical Affect in Samuel Beckett's Prose
突出的虚空:塞缪尔·贝克特散文中的神秘影响
- 批准号:
2883985 - 财政年份:2023
- 资助金额:
$ 47.2万 - 项目类别:
Studentship