Immuno-stromal axes regulate fibroblast heterogeneity in tissue fibrosis and regeneration

免疫基质轴调节组织纤维化和再生中成纤维细胞的异质性

基本信息

  • 批准号:
    10879203
  • 负责人:
  • 金额:
    $ 24.9万
  • 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:
    2022-05-01 至 2026-05-31
  • 项目状态:
    未结题

项目摘要

Project Summary Tissue damage due to injury, disease, or congenital defect continues to be a critical clinical obstacle in human health. Regenerative medicine-based therapies are a promising strategy, yet the critical determinants of success are the immune response and fibrosis. Typically, in tissue repair, inflammation is closely controlled before remodeling by activated fibroblasts, whose presence is also tightly regulated. Immunomodulation is a promising strategy to avoid fibrotic outcomes, yet it is not the immune cells that directly participate in tissue remodeling and collagen production. Therefore, it is critical to understand how immune cells coordinate stromal cells to promote tissue repair or fibrosis. In fibrosis, evidence suggests that chronic immune cell infiltration and proinflammatory cytokines accompany fibroblasts poised to promote fibrosis. Those fibroblasts are characterized by aberrant mechanotransduction (i.e. sensing “normal”/soft as stiff/scarred) leading to the overproduction of ECM. We now know that immune cells and fibroblasts exist as phenotypically distinct subpopulations, including those with a molecular signature tied to fibrosis. Whether inflammatory signals elicit distinct fibroblast subpopulations with aberrant mechanotransduction in fibrosis is unknown and is a key objective. Understanding the relationship between inflammation and fibroblast heterogeneity is essential to predict the regenerative potential of therapies. I hypothesize that fibroblast subpopulations exist during fibrosis with aberrant mechanotransduction that is regulated by inflammatory signaling. During the mentored K99 phase of this application, I will identify the immune and fibroblast subpopulations that emerge during tissue regeneration and fibrosis leveraging non-fibrotic/regenerative microporous annealed particle hydrogels (MAP gels) and fibrotic nonporous bulk hydrogels (NP gels). I will determine the mechanotransductive differences across those subpopulations by purifying them with identified markers and measuring ECM production, myofibroblastic differentiation, integrin activation, and focal adhesion signaling. I will identify signaling pathways necessary for the phenotypes unique to fibroblast subpopulations. I will validate these findings by confirming the identified fibroblast subpopulations and signaling pathways in fibrotic clinical implants. I will continue my scientific and professional development in preparation for the independent phase with consistent guidance from my scientific advisory committee, diversity advisory committee, and collaborators. During the independent phase, I will determine mediators unique to regenerative and fibrotic microenvironments using MAP and NP gels. I determine if IL-1 signaling in fibroblasts is necessary for fibrosis by implanting NP gels in fibroblast-specific IL-1RI knockout mice. I will also determine whether IL-1 signaling is sufficient to promote fibrosis using MAP gels conjugated with IL-1?. We pose an innovative hypothesis that seeks to bridge the gap between inflammation and disrupted mechanotransduction distinctive of fibrotic disorders. This proposal will equip me with scientific and professional training that will enable me to launch a successful and diverse research program as an independent investigator.
项目摘要 由于损伤、疾病或先天缺陷造成的组织损伤仍然是 人类健康。以再生医学为基础的治疗是一种很有前途的策略,但 成功的是免疫反应和纤维化。通常,在组织修复中,炎症受到严密控制。 在被激活的成纤维细胞重塑之前,成纤维细胞的存在也受到严格的调控。免疫调节是一种 有希望避免纤维化结果的策略,但并不是免疫细胞直接参与组织 重塑和胶原蛋白的产生。因此,了解免疫细胞如何协调基质是至关重要的。 促进组织修复或纤维化的细胞。在纤维化方面,有证据表明慢性免疫细胞渗透和 促炎症细胞因子伴随成纤维细胞促进纤维化。这些成纤维细胞的特征是 通过异常的机械转导(即感觉到“正常”/软得僵硬/伤痕累累)导致过量生产 ECM。我们现在知道免疫细胞和成纤维细胞以不同的表型亚群存在,包括 那些具有与纤维化有关的分子特征的人。炎症信号是否能诱导不同的成纤维细胞 纤维化中有异常机械转导的亚群是未知的,也是一个关键的目标。理解 炎症和成纤维细胞异质性之间的关系是预测再生的关键 治疗的潜力。我假设成纤维细胞亚群在纤维化过程中存在异常 受炎症信号调节的机械转导。在此的指导K99阶段 应用程序,我将确定在组织再生和修复过程中出现的免疫和成纤维细胞亚群 利用非纤维化/再生微孔退火颗粒水凝胶(MAP凝胶)和纤维化 无孔块状水凝胶(NP凝胶)。我将确定它们之间的机械传导性差异 通过用已鉴定的标记纯化亚群并测量ECM的产生,肌成纤维细胞 分化、整合素激活和粘着斑信号。我将确定必要的信号通路 成纤维细胞亚群特有的表型。我将通过确认已确认的 纤维化临床植入物中的成纤维细胞亚群和信号通路。我将继续我的科学和 在我的科学指导下,为独立阶段做准备的专业发展 咨询委员会、多样性咨询委员会和合作者。在独立阶段,我将 使用MAP和NP凝胶确定再生和纤维化微环境特有的介体。我决定 通过在成纤维细胞特异性IL-1RI基因敲除中植入NP凝胶,使成纤维细胞中的IL-1信号是纤维化所必需的 老鼠。我还将使用与MAP结合的MAP凝胶来确定IL-1信号是否足以促进纤维化 IL-1?我们提出了一个创新的假设,试图在炎症和破坏之间架起一座桥梁 纤维性疾病特有的机械转导。这项建议将为我配备科学和专业的 培训,这将使我能够启动一个成功的和多样化的研究计划,作为一个独立的调查员。

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 }}

Daniel Abebayehu其他文献

Daniel Abebayehu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('Daniel Abebayehu', 18)}}的其他基金

Immuno-stromal axes regulate fibroblast heterogeneity in tissue fibrosis and regeneration
免疫基质轴调节组织纤维化和再生中成纤维细胞的异质性
  • 批准号:
    10428972
  • 财政年份:
    2022
  • 资助金额:
    $ 24.9万
  • 项目类别:
Inflammatory Cytokines Promotes Pro-Fibrotic Thy-1 Negative Fibroblast Subpopulations In Lung Fibrosis
炎症细胞因子促进肺纤维化中促纤维化 Thy-1 阴性成纤维细胞亚群
  • 批准号:
    10166770
  • 财政年份:
    2019
  • 资助金额:
    $ 24.9万
  • 项目类别:
Inflammatory Cytokines Promotes Pro-Fibrotic Thy-1 Negative Fibroblast Subpopulations In Lung Fibrosis
炎症细胞因子促进肺纤维化中促纤维化 Thy-1 阴性成纤维细胞亚群
  • 批准号:
    9759526
  • 财政年份:
    2019
  • 资助金额:
    $ 24.9万
  • 项目类别:

相似国自然基金

HIF-1α和SDF-1α/CXCR4在调控神经元前体细胞迁移中的作用研究
  • 批准号:
    30800319
  • 批准年份:
    2008
  • 资助金额:
    18.0 万元
  • 项目类别:
    青年科学基金项目
缺血条件下SDF-1/CXCR4轴调控心脏干细胞归巢研究
  • 批准号:
    30800480
  • 批准年份:
    2008
  • 资助金额:
    19.0 万元
  • 项目类别:
    青年科学基金项目
胸腺基质淋巴生成素在乳腺癌患者调节性T细胞分化和Th细胞极化中的作用
  • 批准号:
    30872986
  • 批准年份:
    2008
  • 资助金额:
    30.0 万元
  • 项目类别:
    面上项目

相似海外基金

Investigating bioengineering approaches to produce immuno-modulatory mesenchymal stromal cells and their extracellular vesicle
研究生产免疫调节间充质基质细胞及其细胞外囊泡的生物工程方法
  • 批准号:
    2608627
  • 财政年份:
    2025
  • 资助金额:
    $ 24.9万
  • 项目类别:
    Studentship
Developing functionalised electrospun scaffolds to exploit neural stromal interactions in wound healing
开发功能化电纺支架以利用神经基质相互作用促进伤口愈合
  • 批准号:
    2910663
  • 财政年份:
    2024
  • 资助金额:
    $ 24.9万
  • 项目类别:
    Studentship
Role of Natural Antibodies and B1 cells in Fibroproliferative Lung Disease
天然抗体和 B1 细胞在纤维增生性肺病中的作用
  • 批准号:
    10752129
  • 财政年份:
    2024
  • 资助金额:
    $ 24.9万
  • 项目类别:
Glut1+ cancer associated fibroblasts enforce a metabolic barrier to tumor T cell infiltration
Glut1癌症相关成纤维细胞增强了肿瘤T细胞浸润的代谢屏障
  • 批准号:
    10752508
  • 财政年份:
    2024
  • 资助金额:
    $ 24.9万
  • 项目类别:
早期膵癌におけるstromal-epithelial interactionの分子制御機構の解明
阐明早期胰腺癌基质-上皮相互作用的分子控制机制
  • 批准号:
    24K11123
  • 财政年份:
    2024
  • 资助金额:
    $ 24.9万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
A human tissue-engineered three-layer cornea (hTEC) supplemented with macrophages as a biomaterial for in vitro studies
补充有巨噬细胞的人体组织工程三层角膜(hTEC)作为体外研究的生物材料
  • 批准号:
    488980
  • 财政年份:
    2023
  • 资助金额:
    $ 24.9万
  • 项目类别:
    Operating Grants
Establishment of therapeutic strategy for corneal stromal scaring treatment by applying the ZFP521 gene.
应用ZFP521基因建立角膜基质疤痕治疗策略。
  • 批准号:
    23K09045
  • 财政年份:
    2023
  • 资助金额:
    $ 24.9万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
A study on division of photosynthetic metabolism associated with the uneven distribution of Rubisco and starch in the chloroplast stromal space
叶绿体基质空间中Rubisco和淀粉分布不均与光合代谢划分的研究
  • 批准号:
    23H02195
  • 财政年份:
    2023
  • 资助金额:
    $ 24.9万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
REGULATION OF BONE MARROW MESENCHYMAL STEM CELLS BY VCAM1
VCAM1 对骨髓间充质干细胞的调节
  • 批准号:
    10537391
  • 财政年份:
    2023
  • 资助金额:
    $ 24.9万
  • 项目类别:
Bioorthogonal probe development for highly parallel in vivo imaging
用于高度并行体内成像的生物正交探针开发
  • 批准号:
    10596786
  • 财政年份:
    2023
  • 资助金额:
    $ 24.9万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了