Basement membrane repair dynamics in the Drosophila midgut
果蝇中肠的基底膜修复动力学
基本信息
- 批准号:10689058
- 负责人:
- 金额:$ 3.29万
- 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:2022-09-01 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAdultAppearanceAsthmaBasement membraneBiological AssayBiologyCell Differentiation processCellsClustered Regularly Interspaced Short Palindromic RepeatsCollagen Type IVDataDiabetes MellitusDiseaseDisease ProgressionDrosophila genusElectron MicroscopyEnterocytesEnteroendocrine CellEnzymesEpithelial CellsEpitheliumExtracellular MatrixFat BodyGoodpasture SyndromeHereditary nephritisImageImmunityIntestinesIon ChannelIrritantsKnock-inKnock-outLifeMaintenanceMammalsMatrix MetalloproteinasesMechanical StressMechanicsMetabolismMidgutMorphologyMuscleOrganismPeristalsisPhenotypePopulationProcessProteinsRegulationReportingReproducibilityResistanceRoleShapesSignal TransductionSodium Dextran SulfateSourceStainsStretchingTimeTissuesVisualizationWorkcell typecrosslinkepithelial repairfeedingflygastrointestinal epitheliuminhibitorinsightmutantperoxidasinprecursor cellrepair modelrepairedresponsestem cellstransmission process
项目摘要
Basement membranes are the oldest, most conserved forms of extracellular matrix and serve to separate tissue
layers, direct signals to neighboring cells, insulate tissues from signals, and provide mechanical support. Further,
basement membranes are subject to mechanical damage and require repair. Faulty basement membrane repair
can aid in the progression of diseases such as asthma and diabetes, and diseases of the basement membrane
itself, including Alport syndrome and Goodpasture syndrome. Therefore, understanding how basement
membranes repair will be vital to treating these conditions. My work utilizes the Drosophila midgut basement
membrane to probe repair dynamics. In Drosophila, all major basement membrane components have been
conserved but with less redundancy than mammals. Our lab has developed an assay to reproducibly damage
the basement membrane and study the repair process. Following damage, the basement membrane becomes
less stiff and less dense, indicated by a mechanical stress/strain assay and electron microscopy, respectively.
Previously it was reported that processes required for basement membrane repair are also required to maintain
basement membranes that have not been damaged; these processes include continuous matrix synthesis and
regulation of enzymes (matrix metalloproteinases and peroxidasin). Thus, it is unclear whether basement
membrane damage is actively detected, or instead, passively repaired by homeostatic mechanisms. My
preliminary data suggest basement membrane damage is actively detected. Following damage, the synthesis of
matrix components is upregulated in a specific subset of gut epithelial cells we call matrix-makers, and these
may be the same cells that express a mechanosensory stretch-activated ion channel, Piezo. This raises the
possibility that a change in stiffness of damaged basement membranes signals the initiation of repair. Piezo
knockout flies are able to assemble and maintain basement membranes in the adult fly, but, excitingly, Piezo
knockouts cannot repair basement membranes after damage. This is evidence of a unique mechanism that
detects basement membrane damage and initiates repair. I hypothesize that a loss in matrix stiffness triggers
basement membrane repair mechanisms. In Aim 1, I propose to characterize a transient cell population
responsible for synthesizing new matrix components following basement membrane damage. In Aim 2, I
propose to identify the role of Piezo and its response following basement membrane damage. I expect to identify
the first mechanism for detecting and repairing basement membranes. Understanding this mechanism will
provide fundamental insights into epithelial biology and will be critical to treating and understanding diseases of
the basement membrane.
基底膜是最古老、最保守的细胞外基质形式,用于分隔组织
层,将信号引导至邻近细胞,将组织与信号隔离,并提供机械支撑。更远,
基底膜容易受到机械损伤,需要修复。修复有缺陷的基底膜
可能有助于哮喘和糖尿病等疾病以及基底膜疾病的进展
本身,包括阿尔波特综合征和古德帕斯特综合征。因此,了解地下室如何
膜修复对于治疗这些疾病至关重要。我的工作利用果蝇中肠基底
膜来探测修复动力学。在果蝇中,所有主要的基底膜成分都已被
比哺乳动物保守,但冗余较少。我们的实验室开发了一种可重复损坏的检测方法
基底膜并研究修复过程。受损后,基底膜会变成
分别由机械应力/应变测定和电子显微镜表明,硬度较低且密度较低。
此前有报道称,基底膜修复所需的工艺也需要维持
未受损的基底膜;这些过程包括连续基质合成和
酶的调节(基质金属蛋白酶和过氧化物酶)。因此,尚不清楚地下室是否
膜损伤被主动检测,或者通过稳态机制被动修复。我的
初步数据表明基底膜损伤已被主动检测到。损伤后,合成
基质成分在我们称为基质制造者的特定肠道上皮细胞亚群中上调,这些
可能是表达机械感觉拉伸激活离子通道 Piezo 的相同细胞。这提高了
受损基底膜硬度的变化可能标志着修复的开始。压电
敲除果蝇能够在成年果蝇中组装和维持基底膜,但是,令人兴奋的是,压电
敲除法无法修复受损后的基底膜。这是一种独特机制的证据
检测基底膜损伤并启动修复。我假设基质刚度的损失会触发
基底膜修复机制。在目标 1 中,我建议描述瞬时细胞群的特征
负责在基底膜损伤后合成新的基质成分。在目标 2 中,我
建议确定压电的作用及其在基底膜损伤后的反应。我希望能够识别出
第一个检测和修复基底膜的机制。了解这个机制将
提供对上皮生物学的基本见解,对于治疗和理解以下疾病至关重要
基底膜。
项目成果
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AUBRIE STRICKER的其他文献
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{{ truncateString('AUBRIE STRICKER', 18)}}的其他基金
Basement membrane repair dynamics in the Drosophila midgut
果蝇中肠的基底膜修复动力学
- 批准号:
10537188 - 财政年份:2022
- 资助金额:
$ 3.29万 - 项目类别:
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