IL-17C mediated mechanisms of inflammation

IL-17C 介导的炎症机制

基本信息

  • 批准号:
    8636995
  • 负责人:
  • 金额:
    $ 39.62万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-04-01 至 2018-03-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): IL-17C is a novel and functionally distinct member of the IL-17 family of cytokines and acts through IL- 17RE and IL-17RA to promote innate defense in epithelial cells and regulate Th17 cell differentiation. In human psoriasis tissue, IL-17C is highly expressed in lesional skin and localizes to and exerts effects upon keratinocytes (KCs), endothelial cell (ECs) and leukocytes. Our preliminary data demonstrates increases in CD4+ T cell-derived IL-17A and IL-22 (Th17 and Th22) and EC-derived TNFa following IL-17C stimulation. Interestingly, KCs stimulated with IL-17C and TNF¿ produce similar synergistic inflammatory gene response patterns as those elicited by IL-17A/TNF¿ (but at higher magnitudes) and these gene response patterns are further enhanced with the addition of IL-17A, indicating a positive pro-inflammatory feedback loop between the endothelium, epidermis and Th17/22 cells. In psoriasis patients treated with TNFa inhibitors, cutaneous IL-17C expression decreases rapidly (within 72h) prior to skin improvement and decreases in serum levels of IL-17A and IL-22 suggesting IL-17C may serve as a novel mechanism for amplifying Th17/22/TNFa mediated inflammatory signaling critical for psoriasis pathogenesis. To further explore the importance of IL-17C in mediating psoriasiform inflammation, we genetically engineered mice to overexpress IL-17C in KCs. Murine skin develops well demarcated areas of uninvolved tissue, characterized by increased angiogenesis and modest leukocyte infiltration in the absence of epidermal hyperplasia as well as adjacent areas of involved skin that exhibit robust epidermal hyperplasia, increased leukocyte infiltration and increases in TNFa, IL-17A, and IL-22; suggesting that IL-17C, when coupled with other pro-inflammatory signals, leads to the development of psoriasiform skin dermatitis. Taken together, these observations suggest that IL-17C is a rapidly responsive member of the IL-17 family and that it synergistically activates a proinflammatory feedback loop between KCs, the endothelium and Th17/22 cells and may be critical in psoriasis. We will use this innovative new mouse model, genetic knockout approaches, cre-lox technologies and antibody targeting strategies coupled with in vitro cell co-culture, SiRNA, cell signaling and bioassay approaches to test the hypothesis that: IL-17C binding IL-17RE/A on target cells up regulates TNF¿ (EC) and IL-17/IL-22 (Th17/22) that combine synergistically with IL-17C to induce KC activation and epidermal hyperplasia. We intend to identify IL-17C as a critical early upstream proinflammatory cytokine required for initiating and sustaining chronic skin inflammation, and identify the key cellular targets affected by IL-17C as well as the potential mechanism(s) used to direct KC, EC and Th17/22 cell responses that translate to sustaining inflammation and acanthosis in psoriasis. This work will provide the basis and justification for future work exploring the potential of targeting IL-17C or IL-17RE for therapeutic development for the treatment of psoriasis.
描述(由申请人提供):IL-17 C是细胞因子IL-17家族的一种新的和功能上不同的成员,并通过IL-17 RE和IL-17 RA起作用,以促进上皮细胞中的先天防御并调节Th 17细胞分化。在人类银屑病组织中,IL-17 C在皮损皮肤中高度表达,并定位于角质形成细胞(KC)、内皮细胞(EC)和白细胞并对其发挥作用。我们的初步数据表明,在IL-17 C刺激后,CD 4 + T细胞衍生的IL-17 A和IL-22(Th 17和Th 22)以及EC衍生的TNF α增加。有趣的是,用IL-17 C和TNF?刺激的KC产生与由IL-17 A/TNF?引起的那些相似的协同炎性基因应答模式(但在更高的量级上),并且这些基因应答模式随着IL-17 A的添加而进一步增强,表明内皮、表皮和Th 17/22细胞之间的正促炎反馈回路。在用TNFa抑制剂治疗的银屑病患者中,皮肤IL-17 C表达在皮肤改善之前迅速降低(在72小时内),并且IL-17 A和IL-22的血清水平降低,这表明IL-17 C可能充当放大Th 17/22/TNFa介导的对银屑病发病机制至关重要的炎性信号传导的新机制。为了进一步探索IL-17 C在介导银屑病样炎症中的重要性,我们对小鼠进行基因工程改造,使其在KC中过表达IL-17 C。鼠皮肤发育未受累组织的界限清楚的区域,其特征在于在没有表皮增生的情况下增加的血管生成和适度的白细胞浸润,以及受累皮肤的邻近区域,其表现出强烈的表皮增生、增加的白细胞浸润和TNF α、IL-17 A和IL-22的增加;提示IL-17 C与其它促炎信号结合时导致银屑病样皮肤皮炎的发展。综上所述,这些观察结果表明,IL-17 C是IL-17家族的快速反应成员,并且它协同激活KC、内皮细胞和Th 17/22细胞之间的促炎反馈回路,并且在银屑病中可能是关键的。 我们将使用这种创新的新小鼠模型,基因敲除方法,cre-lox技术和抗体靶向策略,结合体外细胞共培养,SiRNA,细胞信号传导和生物测定方法来测试假设:IL-17 C结合靶细胞上的IL-17 RE/A上调TNF?(EC)和IL-17/IL-22(Th 17/22),其与IL-17 C协同结合联合收割机以诱导KC活化和表皮增生。我们打算确定IL-17 C作为启动和维持慢性皮肤炎症所需的关键早期上游促炎细胞因子,并确定受影响的关键细胞靶点。 通过IL-17 C以及用于指导KC、EC和Th 17/22细胞应答的潜在机制,这些应答转化为银屑病中持续的炎症和棘皮症。这项工作将为将来探索靶向IL-17 C或IL-17 RE治疗银屑病的治疗开发潜力的工作提供基础和理由。

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 }}

Nicole Leanne Ward其他文献

Nicole Leanne Ward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('Nicole Leanne Ward', 18)}}的其他基金

Kallikrein-PAR interactions in skin inflammation
激肽释放酶-PAR 在皮肤炎症中的相互作用
  • 批准号:
    10208722
  • 财政年份:
    2018
  • 资助金额:
    $ 39.62万
  • 项目类别:
Kallikrein-PAR interactions in skin inflammation
激肽释放酶-PAR 在皮肤炎症中的相互作用
  • 批准号:
    10615327
  • 财政年份:
    2018
  • 资助金额:
    $ 39.62万
  • 项目类别:
Kallikrein-PAR interactions in skin inflammation
激肽释放酶-PAR 在皮肤炎症中的相互作用
  • 批准号:
    10449979
  • 财政年份:
    2018
  • 资助金额:
    $ 39.62万
  • 项目类别:
Core 1: Pre-clinical Modeling Core
核心 1:临床前建模核心
  • 批准号:
    10005123
  • 财政年份:
    2017
  • 资助金额:
    $ 39.62万
  • 项目类别:
Project 1: Host Immune Response to Chronic Psoriasis Inflammation
项目 1:宿主对慢性银屑病炎症的免疫反应
  • 批准号:
    10259876
  • 财政年份:
    2017
  • 资助金额:
    $ 39.62万
  • 项目类别:
Project 1: Host Immune Response to Chronic Psoriasis Inflammation
项目 1:宿主对慢性银屑病炎症的免疫反应
  • 批准号:
    10005125
  • 财政年份:
    2017
  • 资助金额:
    $ 39.62万
  • 项目类别:
Core 1: Pre-clinical Modeling Core
核心 1:临床前建模核心
  • 批准号:
    10259874
  • 财政年份:
    2017
  • 资助金额:
    $ 39.62万
  • 项目类别:
IL-17C mediated mechanisms of inflammation
IL-17C 介导的炎症机制
  • 批准号:
    8445590
  • 财政年份:
    2013
  • 资助金额:
    $ 39.62万
  • 项目类别:
Neurogenic inflammation and psoriasiform dermatitis
神经源性炎症和牛皮癣样皮炎
  • 批准号:
    8706044
  • 财政年份:
    2013
  • 资助金额:
    $ 39.62万
  • 项目类别:
IL-17C mediated mechanisms of inflammation
IL-17C 介导的炎症机制
  • 批准号:
    9039538
  • 财政年份:
    2013
  • 资助金额:
    $ 39.62万
  • 项目类别:

相似海外基金

Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
  • 批准号:
    MR/S03398X/2
  • 财政年份:
    2024
  • 资助金额:
    $ 39.62万
  • 项目类别:
    Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
  • 批准号:
    EP/Y001486/1
  • 财政年份:
    2024
  • 资助金额:
    $ 39.62万
  • 项目类别:
    Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
  • 批准号:
    2338423
  • 财政年份:
    2024
  • 资助金额:
    $ 39.62万
  • 项目类别:
    Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
  • 批准号:
    MR/X03657X/1
  • 财政年份:
    2024
  • 资助金额:
    $ 39.62万
  • 项目类别:
    Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
  • 批准号:
    2348066
  • 财政年份:
    2024
  • 资助金额:
    $ 39.62万
  • 项目类别:
    Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
  • 批准号:
    AH/Z505481/1
  • 财政年份:
    2024
  • 资助金额:
    $ 39.62万
  • 项目类别:
    Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10107647
  • 财政年份:
    2024
  • 资助金额:
    $ 39.62万
  • 项目类别:
    EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
  • 批准号:
    2341402
  • 财政年份:
    2024
  • 资助金额:
    $ 39.62万
  • 项目类别:
    Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10106221
  • 财政年份:
    2024
  • 资助金额:
    $ 39.62万
  • 项目类别:
    EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
  • 批准号:
    AH/Z505341/1
  • 财政年份:
    2024
  • 资助金额:
    $ 39.62万
  • 项目类别:
    Research Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了