Impact of polyamines on ILC3 function at steady state and in preclinical model of colitis

多胺对稳态和结肠炎临床前模型中 ILC3 功能的影响

基本信息

  • 批准号:
    10623342
  • 负责人:
  • 金额:
    $ 23.38万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-05-17 至 2024-04-30
  • 项目状态:
    已结题

项目摘要

ABSTRACT IBDs affect 1.3% of U.S. adults. Despite the success of antibody therapies targeting TNFα and IL-23, a significant fraction of patients does not achieve remission, necessitating the search for novel pathogenic pathways that can be targeted. The pathogenesis of IBD is dependent on proper regulation of intestinal immunity. Given their constitutive presence in the intestinal mucosa, group 3 innate lymphoid cells (ILC3) play a pivotal role in maintaining intestinal homeostasis. ILC3 are vital for defense against extracellular bacteria through the secretion of IL-17 and IL-22. However, in mouse models of innate immune colitis, inappropriate activation of ILC3 is a main driver of pathology. Thus, a comprehensive understanding of ILC3 biology is crucial for potentially targeting their role in IBD. Due to their proximity to the intestinal lumen, ILC3 make a number of metabolic adaptations to accommodate the surrounding environment. To systematically characterize these adaptations, we performed untargeted metabolomic profiling of the major intestinal ILC subsets. In combination with analysis of previously generated RNA- sequencing data from intestinal ILCs, we identified a significant enrichment of polyamines and polyamine metabolic enzymes in ILC3. Polyamines are products of arginine metabolism with diverse functions in cancer, aging, and autoimmunity. Mechanistically, they participate in proliferation, chromatin accessibility, as well as translation elongation and termination. Preliminary data shows that dietary polyamines positively regulate the abundance of ILC3. We also found that inhibition of polyamine synthesis using the drug DFMO impairs IL-22 production by ILC3. Furthermore, administration of DFMO in vivo has been shown to exacerbate infection by the intestinal pathogen C. rodentium. Considering these premises, we hypothesize that polyamines positively regulate ILC3 function and contribute to the immunoregulatory role of ILC3 in colitis. We will interrogate these hypotheses in the following aims: Aim 1: To evaluate the impact of intracellular polyamines on ILC3 function at steady state. Synthesis of polyamines is dependent on the rate-limiting enzyme ODC1. We have generated RorcCreOdc1flox/flox mice, in which polyamine biosynthesis is genetically ablated in all conventional T cells and ILC3. By studying these mice (Odc1ΔILC3/T), we will selectively interrogate the importance of polyamines in abundance, functional capacity and proliferation of ILC3. Aim 2: To assess the contribution of ILC3-intrinsic polyamine metabolism in a model of infectious colitis. We will assess the function of Odc1-deficient ILC3 during a model of attaching effacing bacterial colitis, the C. rodentium model, which is highly dependent on ILC3-derived IL-22 for protection. These studies will further our understanding of the metabolic adaptations of ILC3 as well as the potential role for targeting these metabolic pathways to treat inflammatory bowel diseases.
摘要 IBD影响1.3%的美国成年人。尽管靶向TNFα和IL-23的抗体疗法取得了成功, 很大一部分患者没有达到缓解,需要寻找新的致病性 可以有针对性的途径。IBD的发病机制依赖于肠道的适当调节, 免疫力考虑到它们在肠粘膜中的组成性存在,第3组先天淋巴样细胞(ILC 3) 在维持肠道内环境稳定方面起着关键作用。ILC 3对于防御细胞外 细菌通过分泌IL-17和IL-22。然而,在先天免疫性结肠炎的小鼠模型中, ILC 3的不适当激活是病理学的主要驱动因素。因此,全面了解 ILC 3生物学特性对于潜在靶向其在IBD中的作用至关重要。由于它们靠近肠道 在管腔中,ILC 3进行许多代谢适应以适应周围环境, 环境为了系统地描述这些适应,我们进行了非靶向代谢组学研究。 主要肠ILC亚群的分析。结合对先前生成的RNA的分析, 根据肠ILC的测序数据,我们鉴定了多胺的显著富集, ILC 3多胺代谢酶。多胺是精氨酸代谢的产物, 在癌症、衰老和自身免疫中的作用。从机制上讲,它们参与了扩散, 染色质可及性以及翻译延伸和终止。初步数据显示, 膳食多胺正调节ILC 3的丰度。我们还发现多胺的抑制作用 使用药物DFMO的合成损害了ILC 3的IL-22产生。此外,行政 DFMO在体内已被证明会加剧肠道病原体C的感染。啮齿动物。 考虑到这些前提,我们假设多胺正调控ILC 3功能 并有助于ILC 3在结肠炎中的免疫调节作用。我们将质疑这些假设 目的1:评估细胞内多胺对ILC 3功能的影响, 稳态多胺的合成依赖于限速酶ODC 1。我们有 产生的RorcCreOdc 1flox/flox小鼠,其中多胺生物合成在所有基因中均被基因消除, 常规T细胞和ILC 3。通过研究这些小鼠(Odc 1 Δ ILC 3/T),我们将选择性地询问 多胺在ILC 3的丰度、功能能力和增殖中的重要性。目标2:评估 ILC 3-内在多胺代谢在感染性结肠炎模型中的作用。我们将评估 Odc 1缺陷型ILC 3在附着消退性细菌性结肠炎模型中的功能,C. 啮齿动物模型,其高度依赖于ILC 3衍生的IL-22的保护。这些研究将 进一步了解ILC 3的代谢适应以及靶向的潜在作用, 这些代谢途径来治疗炎症性肠病。

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)
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 }}

MARCO COLONNA其他文献

MARCO COLONNA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('MARCO COLONNA', 18)}}的其他基金

Mucosal Immune Defense Mechanisms of the Urinary Bladder
膀胱粘膜免疫防御机制
  • 批准号:
    10587639
  • 财政年份:
    2023
  • 资助金额:
    $ 23.38万
  • 项目类别:
Soluble TREM2 regulation of microglial function in Alzheimer disease
可溶性 TREM2 对阿尔茨海默病小胶质细胞功能的调节
  • 批准号:
    10432584
  • 财政年份:
    2022
  • 资助金额:
    $ 23.38万
  • 项目类别:
Impact of polyamines on ILC3 function at steady state and in preclinical model of colitis
多胺对稳态和结肠炎临床前模型中 ILC3 功能的影响
  • 批准号:
    10528082
  • 财政年份:
    2022
  • 资助金额:
    $ 23.38万
  • 项目类别:
The protein tyrosine kinase SYK drives innate immune responses against Alzheimer's Disease
蛋白质酪氨酸激酶 SYK 驱动针对阿尔茨海默病的先天免疫反应
  • 批准号:
    10674689
  • 财政年份:
    2022
  • 资助金额:
    $ 23.38万
  • 项目类别:
Ontogenetic niche of B cells at the CNS borders in homeostasis, aging and autoimmunity
CNS 边界 B 细胞在稳态、衰老和自身免疫中的个体发育生态位
  • 批准号:
    10446266
  • 财政年份:
    2022
  • 资助金额:
    $ 23.38万
  • 项目类别:
Ontogenetic niche of B cells at the CNS borders in homeostasis, aging and autoimmunity
CNS 边界 B 细胞在稳态、衰老和自身免疫中的个体发育生态位
  • 批准号:
    10557870
  • 财政年份:
    2022
  • 资助金额:
    $ 23.38万
  • 项目类别:
MICROBIOTA-DEPENDENT CONTROL OF CLOSTRIDIUM DIFFICILE: THE ROLE OF ACETATE AND IL-22 BINDING PROTEIN
艰难梭菌的微生物群依赖性控制:乙酸盐和 IL-22 结合蛋白的作用
  • 批准号:
    10321553
  • 财政年份:
    2021
  • 资助金额:
    $ 23.38万
  • 项目类别:
Targeting TREM2 to boost anti-cancer therapy
靶向 TREM2 促进抗癌治疗
  • 批准号:
    10477296
  • 财政年份:
    2021
  • 资助金额:
    $ 23.38万
  • 项目类别:
Targeting TREM2 to boost anti-cancer therapy
靶向 TREM2 促进抗癌治疗
  • 批准号:
    10279674
  • 财政年份:
    2021
  • 资助金额:
    $ 23.38万
  • 项目类别:
MICROBIOTA-DEPENDENT CONTROL OF CLOSTRIDIUM DIFFICILE: THE ROLE OF ACETATE AND IL-22 BINDING PROTEIN
艰难梭菌的微生物群依赖性控制:乙酸盐和 IL-22 结合蛋白的作用
  • 批准号:
    10539270
  • 财政年份:
    2021
  • 资助金额:
    $ 23.38万
  • 项目类别:

相似海外基金

Determining 4-Dimensional Foot Loading Profiles of Healthy Adults across Activities of Daily Living
确定健康成年人日常生活活动的 4 维足部负荷曲线
  • 批准号:
    2473795
  • 财政年份:
    2024
  • 资助金额:
    $ 23.38万
  • 项目类别:
    Studentship
Developing a trunk function assessment for hemiplegics. -For improving activities of daily living-
开发偏瘫患者的躯干功能评估。
  • 批准号:
    23K10540
  • 财政年份:
    2023
  • 资助金额:
    $ 23.38万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Relation with the activities of daily living and the subjective values among people with social withdrawal
社交退缩者日常生活活动与主观价值观的关系
  • 批准号:
    23K16596
  • 财政年份:
    2023
  • 资助金额:
    $ 23.38万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
CRII: RI: Understanding Activities of Daily Living in Indoor Scenarios
CRII:RI:了解室内场景中的日常生活活动
  • 批准号:
    2245652
  • 财政年份:
    2023
  • 资助金额:
    $ 23.38万
  • 项目类别:
    Standard Grant
Sources of vulnerability among those using homecare despite having no limitations in Activities of Daily Living. An intersectionality analysis
尽管日常生活活动没有限制,但使用家庭护理的人的脆弱性来源。
  • 批准号:
    499112
  • 财政年份:
    2023
  • 资助金额:
    $ 23.38万
  • 项目类别:
    Operating Grants
Association between Nursing Care and Prognosis and Activities of Daily Living in Acute Stroke patients by using Big Data.
利用大数据研究急性脑卒中患者的护理与预后和日常生活活动的关系。
  • 批准号:
    23K16412
  • 财政年份:
    2023
  • 资助金额:
    $ 23.38万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Effects of a model of nurses-occupational therapists collaborative practice on activities of daily living in elderly patients
护士-职业治疗师合作实践模式对老年患者日常生活活动的影响
  • 批准号:
    22K17540
  • 财政年份:
    2022
  • 资助金额:
    $ 23.38万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Synergizing home health rehabilitation therapy to optimize patients’ activities of daily living
协同家庭健康康复治疗,优化患者的日常生活活动
  • 批准号:
    10429480
  • 财政年份:
    2022
  • 资助金额:
    $ 23.38万
  • 项目类别:
Assessing a Novel Virtual Environment that Primes Individuals Living with AD/ADRD to Accomplish Activities of Daily Living.
评估一种新颖的虚拟环境,该环境可以帮助 AD/ADRD 患者完成日常生活活动。
  • 批准号:
    10668160
  • 财政年份:
    2022
  • 资助金额:
    $ 23.38万
  • 项目类别:
Synergizing home health rehabilitation therapy to optimize patients’ activities of daily living
协同家庭健康康复治疗,优化患者的日常生活活动
  • 批准号:
    10621820
  • 财政年份:
    2022
  • 资助金额:
    $ 23.38万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了