Aryl hydrocarbon receptor and bilirubin as therapeutic target for ICH

芳烃受体和胆红素作为脑出血的治疗靶点

基本信息

项目摘要

After intracerebral hemorrhage (ICH), phago(endo)cytosis of hematoma components [erythrocytes (RBC), hemoglobin (Hb) and heme], by microglia/macrophages (MMΦ) is essential for removal/detoxification of the hematoma, resolution of inflammation, and restoration of brain homeostasis for optimal neurological recovery. Thus, strategies for protecting MMΦ from injury during engulfment of toxic hematoma components is critical for the efficiency of MMΦ in clearing the hematoma after ICH. Upon engulfment of RBC/Hb/heme from the hematoma, MMΦ express heme oxygenase 1 (HO1; encoded by Hmox1), which catabolizes heme to produce large amounts of bilirubin (BrB) within MMΦ. Normally BrB is a beneficial and potent antioxidant; however, when intracellular BrB accumulates to very high concentrations, it may reversibly inhibit HO1 activity, thus reducing MMΦ' function and even precipitate onto biological membranes or nucleic acids (due to its poor water solubility), causing injury and compromising MMΦ' integrity. On the cellular level, BrB acts as an endogenous agonist for a pleotropic transcription factor, aryl hydrocarbon receptor (AhR), a protein that, based on prior research and our preliminary data, plays essential roles in supporting MMΦ for their integrity and function during hematoma clearance to enhance brain recovery after ICH. Our preliminary studies established that intracellularly elevated free BrB in microglia (MΦ), during erythrophagocytosis, activates AhR to promote transcription of BrB handling proteins, ligandins [(LGN/glutathione S-transferases), which bind fBrB to increase its cytosol solubility] and multidrug resistance protein 1 [(Mrp1)14, 15, which mediates efflux of BrB from the intracellular compartment to the extracellular space]. Without fast clearance of intracellularly accumulating fBrB, MΦ are injured and function less efficiently, and produce large amount of proinflammatory factors that could cause severe brain damage. In addition, we established that BrB-activated AhR promotes phagocytosis and upregulates the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of cellular oxidative defense for hematoma detoxification, and a potential therapeutic target for ICH. Furthermore, we established that AhR activity regulates RelB nuclear translocation, suggesting that AhR may also interact with RelB to transactivate genes involving inflammation resolution. Ultimately, using the mouse model of ICH, we found very promising therapeutic benefits of AhR agonist ITE19-21, alone and even more so in combination with the activator of Nrf2 (sulforaphane, SF), regarding neurological outcome and hematoma clearance. Our hypothesis is that after ICH, activation of AhR/RelB in MMΦ during hematoma removal by BrB (or other non-toxic AhR activators) is vital for preserving MMΦ' survival/phagocytic functions, avoiding self-inflicted damage, retention of reparative phenotype, ultimately leading to a more efficient MMΦ-mediated hematoma clearance and repair after ICH. Activation of AhR could be a novel therapeutic target for ICH.
脑出血(ICH)后,血肿成分[红细胞(RBC)]的吞噬(内腔)细胞增多,

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 }}

Jaroslaw Aronowski其他文献

Jaroslaw Aronowski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('Jaroslaw Aronowski', 18)}}的其他基金

Aryl hydrocarbon receptor and bilirubin as therapeutic target for ICH
芳烃受体和胆红素作为脑出血的治疗靶点
  • 批准号:
    10615880
  • 财政年份:
    2021
  • 资助金额:
    $ 46.49万
  • 项目类别:
Aryl hydrocarbon receptor and bilirubin as therapeutic target for ICH
芳烃受体和胆红素作为脑出血的治疗靶点
  • 批准号:
    10408850
  • 财政年份:
    2021
  • 资助金额:
    $ 46.49万
  • 项目类别:
Humanin and Intracerebral Hemorrhage
护脑素与脑出血
  • 批准号:
    10316990
  • 财政年份:
    2019
  • 资助金额:
    $ 46.49万
  • 项目类别:
Humanin and Intracerebral Hemorrhage
护脑素与脑出血
  • 批准号:
    10547749
  • 财政年份:
    2019
  • 资助金额:
    $ 46.49万
  • 项目类别:
Stroke Preclinical Assessment Network (SPAN) – Tacilizumab for treatment of acute ischemic stroke
卒中临床前评估网络 (SPAN) – 他珠单抗治疗急性缺血性卒中
  • 批准号:
    10214711
  • 财政年份:
    2019
  • 资助金额:
    $ 46.49万
  • 项目类别:
Neutrophils in Recovery after ICH
ICH后中性粒细胞的恢复
  • 批准号:
    9816107
  • 财政年份:
    2016
  • 资助金额:
    $ 46.49万
  • 项目类别:
Optimized lactoferrin for treatment of intracerebral hemorrhage
优化乳铁蛋白治疗脑出血
  • 批准号:
    9016473
  • 财政年份:
    2015
  • 资助金额:
    $ 46.49万
  • 项目类别:
Optimized lactoferrin for treatment of intracerebral hemorrhage
优化乳铁蛋白治疗脑出血
  • 批准号:
    9248446
  • 财政年份:
    2014
  • 资助金额:
    $ 46.49万
  • 项目类别:
Optimized lactoferrin for treatment of intracerebral hemorrhage
优化乳铁蛋白治疗脑出血
  • 批准号:
    8831091
  • 财政年份:
    2014
  • 资助金额:
    $ 46.49万
  • 项目类别:
Treatment of secondary injury after ischemic stroke through targeting microglia
通过靶向小胶质细胞治疗缺血性中风后继发性损伤
  • 批准号:
    8573537
  • 财政年份:
    2013
  • 资助金额:
    $ 46.49万
  • 项目类别:

相似海外基金

Hormone therapy, age of menopause, previous parity, and APOE genotype affect cognition in aging humans.
激素治疗、绝经年龄、既往产次和 APOE 基因型会影响老年人的认知。
  • 批准号:
    495182
  • 财政年份:
    2023
  • 资助金额:
    $ 46.49万
  • 项目类别:
Investigating how alternative splicing processes affect cartilage biology from development to old age
研究选择性剪接过程如何影响从发育到老年的软骨生物学
  • 批准号:
    2601817
  • 财政年份:
    2021
  • 资助金额:
    $ 46.49万
  • 项目类别:
    Studentship
RAPID: Coronavirus Risk Communication: How Age and Communication Format Affect Risk Perception and Behaviors
RAPID:冠状病毒风险沟通:年龄和沟通方式如何影响风险认知和行为
  • 批准号:
    2029039
  • 财政年份:
    2020
  • 资助金额:
    $ 46.49万
  • 项目类别:
    Standard Grant
Neighborhood and Parent Variables Affect Low-Income Preschool Age Child Physical Activity
社区和家长变量影响低收入学龄前儿童的身体活动
  • 批准号:
    9888417
  • 财政年份:
    2019
  • 资助金额:
    $ 46.49万
  • 项目类别:
The affect of Age related hearing loss for cognitive function
年龄相关性听力损失对认知功能的影响
  • 批准号:
    17K11318
  • 财政年份:
    2017
  • 资助金额:
    $ 46.49万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Affect regulation and Beta Amyloid: Maturational Factors in Aging and Age-Related Pathology
影响调节和 β 淀粉样蛋白:衰老和年龄相关病理学中的成熟因素
  • 批准号:
    9320090
  • 财政年份:
    2017
  • 资助金额:
    $ 46.49万
  • 项目类别:
Affect regulation and Beta Amyloid: Maturational Factors in Aging and Age-Related Pathology
影响调节和 β 淀粉样蛋白:衰老和年龄相关病理学中的成熟因素
  • 批准号:
    10166936
  • 财政年份:
    2017
  • 资助金额:
    $ 46.49万
  • 项目类别:
Affect regulation and Beta Amyloid: Maturational Factors in Aging and Age-Related Pathology
影响调节和 β 淀粉样蛋白:衰老和年龄相关病理学中的成熟因素
  • 批准号:
    9761593
  • 财政年份:
    2017
  • 资助金额:
    $ 46.49万
  • 项目类别:
How age dependent molecular changes in T follicular helper cells affect their function
滤泡辅助 T 细胞的年龄依赖性分子变化如何影响其功能
  • 批准号:
    BB/M50306X/1
  • 财政年份:
    2014
  • 资助金额:
    $ 46.49万
  • 项目类别:
    Training Grant
Inflamm-aging: What do we know about the effect of inflammation on HIV treatment and disease as we age, and how does this affect our search for a Cure?
炎症衰老:随着年龄的增长,我们对炎症对艾滋病毒治疗和疾病的影响了解多少?这对我们寻找治愈方法有何影响?
  • 批准号:
    288272
  • 财政年份:
    2013
  • 资助金额:
    $ 46.49万
  • 项目类别:
    Miscellaneous Programs
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了