Damage-Associated Molecular Patterns Driving Fibrosis Progression in Scleroderma

驱动硬皮病纤维化进展的损伤相关分子模式

基本信息

  • 批准号:
    10328406
  • 负责人:
  • 金额:
    $ 46.33万
  • 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:
    2021-01-13 至 2024-04-30
  • 项目状态:
    已结题

项目摘要

June 3 2018 ABSTRACT Synchronous fibrosis in multiple organs is the defining hallmark of systemic sclerosis (SSc), but its pathogenesis remains poorly understood, and there is an urgent need to discover “druggable” targets. The pattern recognition receptor Toll-like receptor 4 (TLR4), a vital mediator of innate immunity, is expressed on both immune and stromal cells, and can be activated by endogenous ligands called “damage-associated molecular patterns” (DAMPs). Published and preliminary work from our laboratories show that TLR4 and its endogenous ligand tenascin-C are likely to play important roles in multi-organ fibrosis in SSc. Notably, tenascin-C itself elicits core fibrotic responses including ECM production and matrix stiffening in fibroblasts and 3D human skin organoid models. TLR4 activity is regulated by the ubiquitin-editing enzyme A20, which is a major risk gene for SSc. However, the mechanism linking SSc-associated A20 variants and pathogenesis are unknown. We demonstrated that A20 expression is reduced in SSc skin biopsies. Surprisingly, we found that A20 inhibited core fibrotic responses, and mice that are haploinsufficient for A20 showed markedly aggravated non- inflammatory skin fibrosis. We hypothesize that persistence of fibrosis in SSc could be explained by activated TLR4 signaling that is triggered by tenascin-C and other DAMPs, and chronically sustained by impaired A20 function. The cell types with increased profibrotic TLR4 pathway activity, and the ensemble of profibrotic DAMPs and specific domains, remain unknown. Moreover, the clinical correlates of reduced A20 in SSc, cell type-specific regulation and anti-fibrotic activity of A20, and the mechanisms linking reduced A20 and SSc pathogenesis, have never been investigated. To address these critical gaps, Aim 1 will determine cell type- and stimulus-specific roles and mechanisms of DAMP-TLR4 signaling in two separate models of experimentally-induced multi-organ fibrosis; map key tenascin-C domains and identify additional DAMPs as potential SSc biomarkers and therapeutic targets; Aim 2 will define the clinical correlates of A20 expression in a longitudinal cohort of SSc patients; and define distinct functions of A20 in the fibrotic process using novel A20-deficient and A20 humanized BAC transgenic mice. Aim 3 will determine the cellular sources and function of TLR4 signaling pathway activity in skin and lung from SSc patients and controls. Employing human disease samples from the established Northwestern and Yale Scleroderma Programs, combined with in vitro and in vivo disease models and state-of-the-art technologies including comprehensive matrisome analysis and unbiased single cell RNA sequencing of multiple tissue, our investigative team is poised to generate notable advances in understanding TLR4 signaling in SSc. The information in turn will guide discovery of novel biomarkers and therapies.
2018年6月3日

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 }}

John Varga其他文献

John Varga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('John Varga', 18)}}的其他基金

Metaorganismal TMAO pathway driving scleroderma pathogenesis: novel gene-environment interaction paradigm and therapeutic target
代谢有机TMAO途径驱动硬皮病发病机制:新的基因-环境相互作用范式和治疗靶点
  • 批准号:
    10440822
  • 财政年份:
    2021
  • 资助金额:
    $ 46.33万
  • 项目类别:
Damage-Associated Molecular Patterns Driving Fibrosis Progression in Scleroderma
驱动硬皮病纤维化进展的损伤相关分子模式
  • 批准号:
    10456232
  • 财政年份:
    2021
  • 资助金额:
    $ 46.33万
  • 项目类别:
Damage-Associated Molecular Patterns Driving Fibrosis Progression in Scleroderma
驱动硬皮病纤维化进展的损伤相关分子模式
  • 批准号:
    10640958
  • 财政年份:
    2021
  • 资助金额:
    $ 46.33万
  • 项目类别:
Metaorganismal TMAO pathway driving scleroderma pathogenesis: novel gene-environment interaction paradigm and therapeutic target
代谢有机TMAO途径驱动硬皮病发病机制:新的基因-环境相互作用范式和治疗靶点
  • 批准号:
    10672805
  • 财政年份:
    2021
  • 资助金额:
    $ 46.33万
  • 项目类别:
Metaorganismal TMAO pathway driving scleroderma pathogenesis: novel gene-environment interaction paradigm and therapeutic target
代谢有机TMAO途径驱动硬皮病发病机制:新的基因-环境相互作用范式和治疗靶点
  • 批准号:
    9912562
  • 财政年份:
    2019
  • 资助金额:
    $ 46.33万
  • 项目类别:
Targeting Adiponectin Signaling: Novel Peptide Therapy for Scleroderma
靶向脂联素信号传导:硬皮病的新型肽疗法
  • 批准号:
    8568554
  • 财政年份:
    2013
  • 资助金额:
    $ 46.33万
  • 项目类别:
Targeting Adiponectin Signaling: Novel Peptide Therapy for Scleroderma
靶向脂联素信号传导:硬皮病的新型肽疗法
  • 批准号:
    8712364
  • 财政年份:
    2013
  • 资助金额:
    $ 46.33万
  • 项目类别:
Fibroblast TGF-beta/Signaling in Scleroderma: Modulation by PPAR-gamma
硬皮病中的成纤维细胞 TGF-β/信号转导:PPAR-gamma 的调节
  • 批准号:
    7814218
  • 财政年份:
    2009
  • 资助金额:
    $ 46.33万
  • 项目类别:
Fibroblast TGF-beta/Smad Signaling in Scleroderma
硬皮病中的成纤维细胞 TGF-β/Smad 信号转导
  • 批准号:
    6660301
  • 财政年份:
    2002
  • 资助金额:
    $ 46.33万
  • 项目类别:
Fibroblast TGF-beta/Smad Signaling in Scleroderma
硬皮病中的成纤维细胞 TGF-β/Smad 信号转导
  • 批准号:
    7106769
  • 财政年份:
    2002
  • 资助金额:
    $ 46.33万
  • 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:
    $ 46.33万
  • 项目类别:
    Fellowship
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:
    $ 46.33万
  • 项目类别:
    Continuing Grant
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:
    $ 46.33万
  • 项目类别:
    Research 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:
    $ 46.33万
  • 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:
    $ 46.33万
  • 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:
    $ 46.33万
  • 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:
    $ 46.33万
  • 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:
    $ 46.33万
  • 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:
    $ 46.33万
  • 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:
    $ 46.33万
  • 项目类别:
    Research Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了