Understanding Interleukin-18 Mediated Susceptibility to Systemic Hyperinflammation
了解 Interleukin-18 介导的全身性过度炎症的易感性
基本信息
- 批准号:10377827
- 负责人:
- 金额:$ 33.13万
- 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:2021-04-01 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:AdjuvantAffectAmericanAntibioticsAutomobile DrivingB-LymphocytesBacterial DNACessation of lifeCharacteristicsChildChildhoodChronicClinicalClinical TrialsComplicationDNA sequencingDataData SetDevelopmentDiseaseEarly DiagnosisEvaluationFecesFunctional disorderGeneticGenetic TranscriptionGoalsHumanHyperactivityIL18 geneImmuneImmunityImmunologic Deficiency SyndromesImmunologicsImmunotherapyImpairmentIndividualInfectionInflammasomeInflammationInflammatoryInterferonsInterleukin-1 betaInterleukin-18InterleukinsIntestinesInvestmentsLifeLymphocyteLymphoid CellMacrophage activation syndromeMeasuresMediatingMicrobeModelingMolecularMorbidity - disease rateMusMyelogenousMyeloid CellsOrganOrganoidsPathway interactionsPatientsPhenotypePhysiologyPredispositionPreventionPrevention strategyProceduresProductionProteinsResearchRheumatismRiskSepsisSerumSourceStem cell transplantSystemic Inflammatory Response SyndromeT-Cell ActivationT-LymphocyteTestingTherapeuticTransgenic Miceadaptive immunitybasecytokinecytotoxiccytotoxicitydysbiosiseffective therapyexperienceexperimental studygain of function mutationgut colonizationgut microbiomehigh riskimmunopathologyimprovedinfancyinnovationinsightintestinal epitheliummicrobialmicrobial colonizationmortalitynovelnovel therapeuticspediatric rheumatic diseasespersonalized diagnosticspreventprotein complexspecific biomarkerssystemic juvenile idiopathic arthritis
项目摘要
PROJECT SUMMARY/ABSTRACT
Despite major investments, the promise of immunotherapy for Systemic Inflammatory Response
Syndrome (SIRS) remains unfulfilled. A hyperinflammatory SIRS subset suffers much higher mortality, and
thus is in greatest need of new therapies to limit immunopathology. The clinical factors used to define
hyperinflammatory SIRS were inspired by a life-threatening complication of pediatric rheumatic disease called
Macrophage Activation Syndrome (MAS). Recently, MAS was genetically associated with hyperactivity of the
NLRC4 inflammasome and excess Interleukin (IL)-18, strongly suggesting that excess IL-18 is a fundamental
host susceptibility factor for hyperinflammatory SIRS. The objectives of this proposal are to identify the relevant
mechanisms driving IL-18 overproduction and to define the pathways by which IL-18 promotes
hyperinflammation. Our central hypothesis is that intestinal IL-18 overproduction promotes both lymphocyte
hyperactivation and dysfunction to drive hyperinflammation and the MAS phenotype. Our guiding rationale is
that understanding the mechanisms driving hyperinflammatory SIRS will enable rational identification of at-risk
patients, identify potential prevention strategies, and facilitate the use of targeted immunotherapies necessary
to prevent organ dysfunction and death.
To accomplish our objectives, we first aim to identify the causes of elevated IL-18 in MAS. This will
involve (i) determining the molecular machinery necessary for inflammasome-driven intestinal overproduction
of IL-18; (ii) isolating the specific microbial factors affecting intestinal IL-18 production and testing their effects
on experimental MAS; (iii) determining the cellular sources (intestinal vs. myeloid) of inducible IL-18 in models
of systemic hyperinflammation; and (iv) correlating systemic IL-18 levels with fecal colonization in children with
Systemic Juvenile Idiopathic Arthritis, who are at high risk for MAS. Our second aim is to define the
mechanisms by which IL-18 promotes hyperinflammation. This will involve (i) determining the immunologic
mechanisms by which IL-18 promotes models of hyperinflammation; (ii) determining how cytotoxic impairment
and excess IL-18 synergistically promote immunopathology; and (iii) determining how NLRC4 hyperactivity and
excess IL-18 promote susceptibility to infection.
These experiments will contribute significantly to defining new genetic and mechanistic drivers of
hyperinflammation, and they will guide precision diagnostics, prevention strategies, and targeted treatments to
prevent morbidity and mortality in hyperinflammatory SIRS. The proposed research is innovative because it
originates with mechanisms derived from monogenic human hyperinflammatory diseases to understand and
manipulate SIRS physiology more broadly. Ultimately, we expect completion of the proposed studies to provide
specific insights useful for guiding early detection of the hyperinflammatory SIRS phenotype and novel means
to disrupt life-threatening immunopathology.
项目摘要/摘要
尽管进行了重大投资,免疫疗法对全身炎症反应的承诺
综合征(SIRS)仍未得到满足。高炎症性SIRS亚群的死亡率要高得多。
因此,最需要新的治疗方法来限制免疫病理学。临床因素用来定义
高炎性SIRS是由一种危及生命的儿科风湿病并发症引起的
巨噬细胞激活综合征(MAS)。最近,MAS在基因上与多动症有关。
NLRC4炎症体和过度的白介素18,强烈表明过度的白介素18是一个基本的
高炎性SIRS的宿主易感因素。这项提案的目标是确定相关的
推动IL-18过度产生的机制和确定IL-18促进的途径
过度炎症。我们的中心假设是肠道IL-18的过度产生促进了这两个淋巴细胞
过度激活和功能障碍导致过度炎症和MAS表型。我们的指导思想是
了解导致高炎症性SIRS的机制将使我们能够理性地识别高危
患者,确定潜在的预防策略,并促进必要的靶向免疫疗法的使用
以防止器官功能障碍和死亡。
为了实现我们的目标,我们首先的目标是确定MAS中IL-18升高的原因。这将是
涉及(I)确定炎症小体驱动的肠道过度生产所必需的分子机制
IL-18的产生;(Ii)分离影响肠道IL-18产生的特定微生物因子并检测其作用
关于实验性MAS;(Iii)在模型中确定诱导性IL-18的细胞来源(肠道与髓系)
系统性炎症;以及(Iv)系统性IL-18水平与儿童粪便定植的相关性
系统性青少年特发性关节炎,是MAS的高危人群。我们的第二个目标是定义
IL-18促进过度炎症的机制。这将涉及(I)确定免疫学
IL-18促进炎症模型的机制;(Ii)确定细胞毒性损伤如何
和过量的IL-18协同促进免疫病理;以及(Iii)确定NLRC4过度活动和
过量的IL-18会增加感染的易感性。
这些实验将大大有助于定义新的遗传和机制驱动因素
高度炎症,他们将指导精确的诊断、预防策略和有针对性的治疗
预防高炎症性SIRS的发病率和死亡率。这项拟议的研究具有创新性,因为它
起源于单基因人类高炎性疾病的机制,以了解和
更广泛地操纵SIRS生理。最终,我们预期建议的研究完成后,可提供
有助于指导早期发现高炎症性SIRS表型和新方法的具体见解
扰乱危及生命的免疫病理。
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 }}
Scott William Canna其他文献
Scott William Canna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('Scott William Canna', 18)}}的其他基金
Understanding Interleukin-18 Mediated Susceptibility to Systemic Hyperinflammation
了解 Interleukin-18 介导的全身性过度炎症的易感性
- 批准号:
10611531 - 财政年份:2021
- 资助金额:
$ 33.13万 - 项目类别:
Understanding Interleukin-18 Mediated Susceptibility to Systemic Hyperinflammation
了解 Interleukin-18 介导的全身性过度炎症的易感性
- 批准号:
10481855 - 财政年份:2021
- 资助金额:
$ 33.13万 - 项目类别:
Understanding Interleukin-18 Mediated Susceptibility to Systemic Hyperinflammation
了解 Interleukin-18 介导的全身性过度炎症的易感性
- 批准号:
9914109 - 财政年份:2019
- 资助金额:
$ 33.13万 - 项目类别:
Mechanisms of NLRC4 inflammasome-associated hyperinflammation
NLRC4炎症小体相关的过度炎症的机制
- 批准号:
9087657 - 财政年份:2017
- 资助金额:
$ 33.13万 - 项目类别:
Mechanisms by which IL-10 limits Toll-like Receptor 9 mediated Macrophage Activat
IL-10 限制 Toll 样受体 9 介导的巨噬细胞激活的机制
- 批准号:
8398178 - 财政年份:2012
- 资助金额:
$ 33.13万 - 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:
$ 33.13万 - 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:
$ 33.13万 - 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:
$ 33.13万 - 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:
$ 33.13万 - 项目类别:
Fellowship
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:
$ 33.13万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
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:
$ 33.13万 - 项目类别:
Research Grant
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:
$ 33.13万 - 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:
$ 33.13万 - 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:
$ 33.13万 - 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:
$ 33.13万 - 项目类别:
Studentship