Sox9 Regulation of Fibroblast Activation and Pulmonary Fibrosis
Sox9 对成纤维细胞活化和肺纤维化的调节
基本信息
- 批准号:10768171
- 负责人:
- 金额:$ 49.55万
- 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:2021-08-15 至 2026-05-31
- 项目状态:未结题
- 来源:
- 关键词:
项目摘要
PROJECT SUMMARY
Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disease that is incurable and progressive due to
fibroblast activation, and the formation of scar tissue. Approximately 130,000 Americans suffer from IPF, with
an estimated 50,000 new cases diagnosed each year. Although it is well accepted that myofibroblast
accumulation is a central component of pathogenesis in IPF, the transcriptional program(s) that orchestrate
fibroblast activation including fibroblast-to-myofibroblast transformation (FMT), survival, migration and ECM
organization are poorly defined and represent a significant knowledge gap in the field. Sox9 is a member of the
HMG-box family of transcription factors that are selectively expressed by epithelial progenitor cells to modulate
branching morphogenesis in the lung and the organized deposition of collagen as part of cartilage formation in
multiple organs. However, the role of Sox9 in fibroblast activation has been poorly studied in adult fibrotic lung
diseases. Our new findings have determined that Sox9 is upregulated in lung mesenchymal cells of IPF and
functions as a positive regulator of FMT, myofibroblast survival, migration and ECM production. The loss of
Sox9 expression has attenuated αSMA expression and myofibroblast transformation in mesenchymal cells
isolated from IPF lungs and TGFα model. In support, a recent published study suggest Sox9 upregulation in
patients with chronic liver disease that correlated with fibrosis severity and progression towards cirrhosis.
Taken together, these findings lead us to postulate that Sox9 functions as a positive regulator of FMT,
myofibroblast survival, migration, and ECM in the pathogenesis of pulmonary fibrosis. For this study,
we propose three specific aims: 1) determine mechanisms by which Sox9 induces fibroblast activation; 2)
establish in vivo the role of Sox9-expressing mesenchymal cells in the pathogenesis of pulmonary fibrosis; and
3) identify mechanisms by which Sox9 augments myofibroblast survival and the progression of established and
ongoing pulmonary fibrosis. We will use advanced molecular methods and mouse transgenic approaches,
coupled with detailed biochemical analysis of these Sox9-driven processes in vivo and in vitro. Completion of
the proposed experiments is likely to impart a significant understanding of Sox9-driven fibroblast activation.
The multidisciplinary team will facilitate a timely approach with expertise in all aspects of lung pathology and
support future translational studies in IPF. Our approach is innovative due to the generation of novel transgenic
mice to test mesenchymal cell-specific functions of Sox9 in pulmonary fibrosis. The proposed research is
significant in that completion of this study will increase an understanding of the mechanisms causing fibroblast
activation in IPF, which in turn will lead to advanced medical therapies for the treatment and possible cure or
prevention of this debilitating lung disease.
项目摘要
特发性肺纤维化(IPF)是一种致命的纤维化肺病,由于肺纤维化,
成纤维细胞活化和瘢痕组织的形成。大约13万美国人患有IPF,
估计每年有5万个新病例被诊断出来。虽然肌成纤维细胞
蓄积是IPF发病机制的核心组成部分,
成纤维细胞活化,包括成纤维细胞向肌成纤维细胞转化(FMT)、存活、迁移和ECM
该组织的定义不明确,代表了该领域的重大知识差距。Sox 9是
上皮祖细胞选择性表达的HMG-盒转录因子家族,
肺中的分支形态发生和作为软骨形成的一部分的胶原蛋白的有组织沉积,
多个器官然而,Sox 9在成纤维细胞活化中的作用在成人纤维化肺中的研究很少。
疾病我们的新发现已经确定Sox 9在IPF的肺间充质细胞中上调,
作为FMT、肌成纤维细胞存活、迁移和ECM产生的正调节剂起作用。的损失
Sox 9表达减弱了间充质细胞中αSMA的表达和肌成纤维细胞转化
分离自IPF肺和TGFα模型。最近发表的一项研究表明,Sox 9在人乳腺癌中上调,
与纤维化严重程度和向肝硬化进展相关的慢性肝病患者。
综上所述,这些发现使我们假设Sox 9作为FMT的正调节因子发挥作用,
肺纤维化发病机制中的肌成纤维细胞存活、迁移和ECM。对于这项研究,
我们提出了三个具体目标:1)确定Sox 9诱导成纤维细胞活化的机制; 2)
在体内确定表达Sox 9的间充质细胞在肺纤维化发病机制中的作用;以及
3)确定Sox 9增强肌成纤维细胞存活和已建立的
持续性肺纤维化我们将使用先进的分子方法和小鼠转基因方法,
结合这些Sox 9驱动的过程在体内和体外的详细的生化分析。完成
所提出的实验可能赋予对Sox 9驱动的成纤维细胞活化的重要理解。
多学科团队将利用肺部病理学各方面的专业知识,
支持未来IPF的转化研究。我们的方法是创新的,由于产生新的转基因,
小鼠以测试Sox 9在肺纤维化中的间充质细胞特异性功能。拟议的研究是
本研究完成将增加对成纤维细胞
激活IPF,这反过来将导致先进的药物治疗和可能的治愈,或
预防这种使人衰弱的肺病。
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 }}
Satish K Madala其他文献
Satish K Madala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('Satish K Madala', 18)}}的其他基金
Sox9 Regulation of Fibroblast Activation and Pulmonary Fibrosis
Sox9 对成纤维细胞活化和肺纤维化的调节
- 批准号:
10180163 - 财政年份:2021
- 资助金额:
$ 49.55万 - 项目类别:
Sox9 Regulation of Fibroblast Activation and Pulmonary Fibrosis
Sox9 对成纤维细胞活化和肺纤维化的调节
- 批准号:
10620706 - 财政年份:2021
- 资助金额:
$ 49.55万 - 项目类别:
Sox9 Regulation of Fibroblast Activation and Pulmonary Fibrosis
Sox9 对成纤维细胞活化和肺纤维化的调节
- 批准号:
10461725 - 财政年份:2021
- 资助金额:
$ 49.55万 - 项目类别:
IL-31 Regulation of Immunopathology in Pulmonary Fibrosis
IL-31 对肺纤维化免疫病理学的调节
- 批准号:
9762810 - 财政年份:2018
- 资助金额:
$ 49.55万 - 项目类别:
THE ROLE OF IL-31 IN TH2 CYTOKINE-DRIVEN SYSTEMIC SCLEROSIS
IL-31 在 TH2 细胞因子驱动的系统性硬化症中的作用
- 批准号:
8850814 - 财政年份:2013
- 资助金额:
$ 49.55万 - 项目类别:
THE ROLE OF IL-31 IN TH2 CYTOKINE-DRIVEN SYSTEMIC SCLEROSIS
IL-31 在 TH2 细胞因子驱动的系统性硬化症中的作用
- 批准号:
8446714 - 财政年份:2013
- 资助金额:
$ 49.55万 - 项目类别:
相似海外基金
Epigenetic and transcriptional regulation of mechanical memory during tissue repair and scarring differs among fibroblast populations
组织修复和疤痕形成过程中机械记忆的表观遗传和转录调节在成纤维细胞群体中存在差异
- 批准号:
MR/X503095/1 - 财政年份:2023
- 资助金额:
$ 49.55万 - 项目类别:
Research Grant
Hypoxic regulation of macrophage migration and function via fibroblast reprogramming in pancreatic cancer
通过胰腺癌成纤维细胞重编程对巨噬细胞迁移和功能的缺氧调节
- 批准号:
10677376 - 财政年份:2023
- 资助金额:
$ 49.55万 - 项目类别:
Elucidating the epigenetic regulation of extracellular matrix and virus-induced fibroblast activation
阐明细胞外基质和病毒诱导的成纤维细胞活化的表观遗传调控
- 批准号:
10572863 - 财政年份:2023
- 资助金额:
$ 49.55万 - 项目类别:
Regulation and role of fibroblast-derived interleukin-33 in the pancreatic tumor microenvironment
成纤维细胞来源的白细胞介素33在胰腺肿瘤微环境中的调节和作用
- 批准号:
10461248 - 财政年份:2022
- 资助金额:
$ 49.55万 - 项目类别:
Regulation of Osteocyte Survival by Fibroblast Growth Factor Signaling Pathways
成纤维细胞生长因子信号通路对骨细胞存活的调节
- 批准号:
10391803 - 财政年份:2022
- 资助金额:
$ 49.55万 - 项目类别:
Transcriptional regulation of fibroblast generation in the embryonic mouse heart.
小鼠胚胎心脏成纤维细胞生成的转录调控。
- 批准号:
RGPIN-2019-06658 - 财政年份:2022
- 资助金额:
$ 49.55万 - 项目类别:
Discovery Grants Program - Individual
Regulation and role of fibroblast-derived interleukin-33 in the pancreatic tumor microenvironment
成纤维细胞来源的白细胞介素33在胰腺肿瘤微环境中的调节和作用
- 批准号:
10604294 - 财政年份:2022
- 资助金额:
$ 49.55万 - 项目类别:
Regulation of Osteocyte Survival by Fibroblast Growth Factor Signaling Pathways
成纤维细胞生长因子信号通路对骨细胞存活的调节
- 批准号:
10577758 - 财政年份:2022
- 资助金额:
$ 49.55万 - 项目类别:
Sox9 Regulation of Fibroblast Activation and Pulmonary Fibrosis
Sox9 对成纤维细胞活化和肺纤维化的调节
- 批准号:
10180163 - 财政年份:2021
- 资助金额:
$ 49.55万 - 项目类别:
Deciphering the Genomics of Gene Network Regulation of T Cell and Fibroblast States in Autoimmune Inflammation
破译自身免疫炎症中 T 细胞和成纤维细胞状态的基因网络调控的基因组学
- 批准号:
10472615 - 财政年份:2021
- 资助金额:
$ 49.55万 - 项目类别: