Interdependency of fibroadipogenic progenitors and extracellular matrix that drive skeletal muscle fibrosis

驱动骨骼肌纤维化的纤维脂肪祖细胞和细胞外基质的相互依赖性

基本信息

  • 批准号:
    10602460
  • 负责人:
  • 金额:
    $ 46.18万
  • 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:
    2022-04-05 至 2027-03-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY Fibrosis is the accumulation of extracellular matrix components that disrupt tissue function and is prevalent across many muscle diseases. Muscle functions compromised in fibrosis include muscles primary function to contract as well as its ability to be compliantly stretched when not active. This results in weak and stiff muscle decreasing mobility and producing joint contractures. Skeletal muscle regenerates following injury from resident muscle stem cells, however those cells are sensitive to the organization and mechanics of fibrotic extracellular matrix. Another muscle resident stem cell, fibro-adipogenic progenitors, support myogenesis following injury, but in the context of fibrosis contribute to the pathologic buildup of extracellular matrix. However, the sensitivity of fibro-adipogenic progenitors to their mechanical environment is unknown. Nor is it known how fibro-adipogenic progenitors production of extracellular matrix signals to muscle stem cells to support or impair myogenesis. In order to target effective anti-fbrotic therapies the mechanisms that of communication between fibro-adipogenic progenitors and the extracellular matrix that defines fibrosis must be revealed. Further, the fibrotic environment can act as a barrier to restorative gene therapies for muscular dystrophy, but how fibrosis may influence the efficacy of promising gene therapies is unknown. Fibrosis is particularly common in Duchenne muscular dystrophy, with associated joint contractures. Yet, even removal of functional dystrophin from more fibrotic mouse strains yields a less severe fibrosis, motivating a conjunction of studies in both mice and humans. Fibro-adipogenic progenitors can be activated into pro- fibrogenic cells to resist apoptotic signals and produce excessive extracellular matrix components. This fibrotic extracellular matrix is mainly made of fibrillar collagen, which is the dominant load-bearing structure within healthy and fibrotic extracellular matrix. However, the organization of collagen fibers in the extracellular matrix can alter both the mechanics and adherent cell phenotypes. Fibro-adipogenic progenitors are similar to mesenchymal stromal cells, yet how extracellular matrix organization and mechanical signals drive conversion to the pro-fibrotic state are not known. Nor is it known how one of the primary functions of fibro-adipogenic progenitors, to secrete extracellular matrix, impacts the muscle stem cells responsible for myogenesis. This the potential to create a positive feedback cycle between fibro-adipogenic protenitors and the extracellular matrix. Promising gene therapy using micro-dystrophin is able to largely restore the integrity of myofibers. However, it isn’t known if once the pro-fibrotic cycle is in place if restoring the myofiber integrity and the initiating signals of fibrosis will be sufficient to reverse prominent fibrosis and the associated decline in function. Thus, our objective is to reveal fibro-adipogenic progenitors-based extracellular matrix contribution to functional decline and lack of regeneration in fibrosis along with the potential to reverse fibrosis in muscular dystrophy. In Aim 1, we will utilize a combination of engineered gels and native decellularized matrices to mimic health and fibrosis to determine both the architectural and mechanical features of a cell substrate that directs fibro- adipogenic progenitor fate. In Aim 2, we will induce pro-fibrotic or pro-regenerative fibro-adipogenic progenitor synthesis of extracellular matrices to determine how their structure influences muscle stem cell myogenesis in fibrosis. In Aim 3, micro-dystrophin gene therapy will be administered to before and after the onset of fibrosis to stratify the functional efficacy and change in fibrosis based on the initial stage of fibro-adipogenic progenitors and fibrosis. Success in these Aims will establish the mechanisms fibro-adipogenic progenitors and extracellular matrix interact to perpetuate progressive fibrosis and identify specific targets for anti-fibrotic therapy development that can restore function and enhance the efficacy of restorative gene therapy in muscular dystrophies.
项目总结 纤维化是细胞外基质成分的积聚,破坏组织功能,并普遍存在 横跨许多肌肉疾病。纤维化中的肌肉功能受损包括肌肉的主要功能 收缩以及在不活动时顺从伸展的能力。这会导致肌肉无力和僵硬。 活动度降低,导致关节痉挛。居民受伤后骨骼肌再生 肌肉干细胞,然而,这些细胞对纤维化细胞外的组织和机制很敏感 矩阵。另一种肌肉干细胞,纤维脂肪前体细胞,支持损伤后的肌肉生成,但 在纤维化的背景下,有助于细胞外基质的病理性堆积。然而,这种敏感度 纤维成脂前体细胞对其机械环境的影响尚不清楚。也不知道纤维脂肪是如何形成的 祖细胞产生细胞外基质信号给肌肉干细胞,以支持或损害肌肉发生。在……里面 为了靶向有效的抗血栓治疗,纤维脂肪生成之间的沟通机制 必须揭示祖细胞和定义纤维化的细胞外基质。此外,纤维化的环境 可以成为肌肉营养不良恢复性基因治疗的障碍,但纤维化可能如何影响 前景看好的基因疗法的疗效尚不清楚。 纤维化在Duchenne肌营养不良症中尤其常见,并伴有关节痉挛。然而,即使是 从更多纤维化的小鼠品系中去除功能性肌营养不良蛋白可以产生不那么严重的纤维化,从而激发 在老鼠和人类身上进行的联合研究。纤维成脂前体细胞可被激活为促- 纤维形成细胞抵抗凋亡信号并产生过多的细胞外基质成分。这是纤维性的 细胞外基质主要由纤维性胶原蛋白组成,胶原蛋白是体内主要的承重结构。 健康和纤维化的细胞外基质。然而,细胞外基质中胶原纤维的组织 可以改变力学和贴壁细胞表型。纤维成脂前体细胞类似于 间充质基质细胞,然而细胞外基质组织和机械信号如何驱动转化 促肝纤维化的状态尚不清楚。也不知道纤维脂肪生成的主要功能之一是 祖细胞分泌细胞外基质,影响负责肌肉发生的肌肉干细胞。这就是 有可能在纤维成脂前体和细胞外基质之间形成正反馈循环。 利用微肌营养不良蛋白进行基因治疗有望在很大程度上恢复肌纤维的完整性。然而,它 目前尚不清楚一旦促纤维化循环到位,是否恢复了肌纤维的完整性和启动信号 纤维化将足以逆转显著的纤维化和相关的功能下降。因此,我们的目标是 揭示以纤维脂肪前体细胞为基础的细胞外基质对功能衰退和缺乏 肌营养不良症的纤维化再生以及逆转纤维化的可能性。 在目标1中,我们将利用工程凝胶和天然脱细胞基质的组合来模拟健康和 纤维化,以确定引导纤维蛋白原的细胞底物的结构和机械特征。 造脂先祖的命运。在目标2中,我们将诱导促纤维化或促再生的纤维成脂前体细胞。 细胞外基质的合成以确定它们的结构如何影响肌肉干细胞的肌肉发生 纤维化症。在目标3中,微肌萎缩蛋白基因治疗将在纤维化发生前后进行,以 基于纤维脂肪前体细胞初始阶段的功能疗效和纤维化改变的分层 和纤维化症。这些目标的成功将建立成纤维脂肪祖细胞和细胞外的机制 基质相互作用使进展性纤维化持续存在,并确定抗纤维化治疗开发的特定靶点 这可以恢复功能,提高恢复性基因治疗肌营养不良症的疗效。

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 }}

LUCAS R SMITH其他文献

LUCAS R SMITH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('LUCAS R SMITH', 18)}}的其他基金

Interdependency of fibroadipogenic progenitors and extracellular matrix that drive skeletal muscle fibrosis
驱动骨骼肌纤维化的纤维脂肪祖细胞和细胞外基质的相互依赖性
  • 批准号:
    10454078
  • 财政年份:
    2022
  • 资助金额:
    $ 46.18万
  • 项目类别:
The role of collagen organization in determination of fibrotic muscle function and regeneration
胶原组织在纤维化肌肉功能和再生测定中的作用
  • 批准号:
    9788030
  • 财政年份:
    2018
  • 资助金额:
    $ 46.18万
  • 项目类别:
The role of collagen organization in determination of fibrotic muscle function and regeneration
胶原组织在纤维化肌肉功能和再生测定中的作用
  • 批准号:
    9982777
  • 财政年份:
    2018
  • 资助金额:
    $ 46.18万
  • 项目类别:
The role of collagen organization in determination of fibrotic muscle function and regeneration
胶原组织在纤维化肌肉功能和再生测定中的作用
  • 批准号:
    9034309
  • 财政年份:
    2016
  • 资助金额:
    $ 46.18万
  • 项目类别:
The role of collagen organization in determination of fibrotic muscle function and regeneration
胶原组织在纤维化肌肉功能和再生测定中的作用
  • 批准号:
    9274036
  • 财政年份:
    2016
  • 资助金额:
    $ 46.18万
  • 项目类别:

相似国自然基金

Epac1/2通过蛋白酶体调控中性粒细胞NETosis和Apoptosis在急性肺损伤中的作用研究
  • 批准号:
    LBY21H010001
  • 批准年份:
    2020
  • 资助金额:
    0.0 万元
  • 项目类别:
    省市级项目
基于Apoptosis/Ferroptosis双重激活效应的天然产物AlbiziabiosideA的抗肿瘤作用机制研究及其结构改造
  • 批准号:
    81703335
  • 批准年份:
    2017
  • 资助金额:
    20.0 万元
  • 项目类别:
    青年科学基金项目
双肝移植后Apoptosis和pyroptosis在移植物萎缩差异中的作用和供受者免疫微环境变化研究
  • 批准号:
    81670594
  • 批准年份:
    2016
  • 资助金额:
    58.0 万元
  • 项目类别:
    面上项目
Serp-2 调控apoptosis和pyroptosis 对肝脏缺血再灌注损伤的保护作用研究
  • 批准号:
    81470791
  • 批准年份:
    2014
  • 资助金额:
    73.0 万元
  • 项目类别:
    面上项目
Apoptosis signal-regulating kinase 1是七氟烷抑制小胶质细胞活化的关键分子靶点?
  • 批准号:
    81301123
  • 批准年份:
    2013
  • 资助金额:
    23.0 万元
  • 项目类别:
    青年科学基金项目
APO-miR(multi-targeting apoptosis-regulatory miRNA)在前列腺癌中的表达和作用
  • 批准号:
    81101529
  • 批准年份:
    2011
  • 资助金额:
    22.0 万元
  • 项目类别:
    青年科学基金项目
放疗与细胞程序性死亡(APOPTOSIS)相关性及其应用研究
  • 批准号:
    39500043
  • 批准年份:
    1995
  • 资助金额:
    9.0 万元
  • 项目类别:
    青年科学基金项目

相似海外基金

Spatial Restriction of Apoptotic Machinery during Neuronal Apoptosis and Pruning
神经元凋亡和修剪过程中凋亡机制的空间限制
  • 批准号:
    10596657
  • 财政年份:
    2021
  • 资助金额:
    $ 46.18万
  • 项目类别:
Spatial Restriction of Apoptotic Machinery during Neuronal Apoptosis and Pruning
神经元凋亡和修剪过程中凋亡机制的空间限制
  • 批准号:
    10417219
  • 财政年份:
    2021
  • 资助金额:
    $ 46.18万
  • 项目类别:
Examining the contribution of apoptosis repressor with caspase recruitment domain (ARC) to the anti-apoptotic effect of endurance training in skeletal muscle
检查具有半胱天冬酶募集结构域 (ARC) 的凋亡抑制因子对骨骼肌耐力训练的抗凋亡作用的贡献
  • 批准号:
    441952-2013
  • 财政年份:
    2015
  • 资助金额:
    $ 46.18万
  • 项目类别:
    Alexander Graham Bell Canada Graduate Scholarships - Doctoral
Understanding the activation of pro-apoptotic Bcl-2 family proteins for the development of modulators of apoptosis
了解促凋亡 Bcl-2 家族蛋白的激活以开发凋亡调节剂
  • 批准号:
    nhmrc : 1059331
  • 财政年份:
    2014
  • 资助金额:
    $ 46.18万
  • 项目类别:
    Project Grants
Examining the contribution of apoptosis repressor with caspase recruitment domain (ARC) to the anti-apoptotic effect of endurance training in skeletal muscle
检查具有半胱天冬酶募集结构域 (ARC) 的凋亡抑制因子对骨骼肌耐力训练的抗凋亡作用的贡献
  • 批准号:
    441952-2013
  • 财政年份:
    2014
  • 资助金额:
    $ 46.18万
  • 项目类别:
    Alexander Graham Bell Canada Graduate Scholarships - Doctoral
Examining the contribution of apoptosis repressor with caspase recruitment domain (ARC) to the anti-apoptotic effect of endurance training in skeletal muscle
检查具有半胱天冬酶募集结构域 (ARC) 的凋亡抑制因子对骨骼肌耐力训练的抗凋亡作用的贡献
  • 批准号:
    441952-2013
  • 财政年份:
    2013
  • 资助金额:
    $ 46.18万
  • 项目类别:
    Postgraduate Scholarships - Doctoral
Apoptotic Osteocytes Promote Chondrocyte Apoptosis via Soluble Factors
凋亡骨细胞通过可溶性因子促进软骨细胞凋亡
  • 批准号:
    251802
  • 财政年份:
    2012
  • 资助金额:
    $ 46.18万
  • 项目类别:
    Studentship Programs
Defining the mechanism(s) by which the cellular inhibitor of apoptosis protein 2 (cIAP2) contributes to early stage atherosclerosis development by directly promoting the participation of key apoptotic pathways within lesion-associated macrophages
确定凋亡蛋白细胞抑制剂 2 (cIAP2) 通过直接促进病变相关巨噬细胞内关键凋亡途径的参与来促进早期动脉粥样硬化发展的机制
  • 批准号:
    191299
  • 财政年份:
    2009
  • 资助金额:
    $ 46.18万
  • 项目类别:
    Operating Grants
ATP release during apoptosis and its relevance to apoptotic cell clearance
凋亡过程中 ATP 释放及其与凋亡细胞清除的相关性
  • 批准号:
    8075522
  • 财政年份:
    2009
  • 资助金额:
    $ 46.18万
  • 项目类别:
ATP release during apoptosis and its relevance to apoptotic cell clearance
凋亡过程中 ATP 释放及其与凋亡细胞清除的相关性
  • 批准号:
    7676912
  • 财政年份:
    2009
  • 资助金额:
    $ 46.18万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了