Targeting redox to resorb ECM
靶向氧化还原再吸收 ECM
基本信息
- 批准号:10382514
- 负责人:
- 金额:$ 6.76万
- 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:2022-01-03 至 2023-01-02
- 项目状态:已结题
- 来源:
- 关键词:AgonistAntibodiesBiogenesisBiologyBleomycinCell Culture TechniquesCellular StressCharacteristicsChestCollagenDataDepositionDetectionDiagnosisDiseaseDopamineDopamine AgonistsDopamine D1 ReceptorEnzymesEquilibriumExtracellular MatrixFibroblastsFibrosisFlavin-Adenine DinucleotideGoalsGrantHistologyHumanHydroxyprolineImageImpairmentImplantIn SituIn VitroLife ExpectancyLinkLungMeasuresMediatingMetabolicMetabolismMicroscopicMitochondriaModelingMonitorMusNicotinamide adenine dinucleotideOpticsOxidation-ReductionOxidative StressOxidesPPAR gammaPathway interactionsPhasePhenotypePlayProteinsPulmonary FibrosisReactive Oxygen SpeciesResolutionRoleSignal TransductionSliceSystemTechniquesTestingTherapeuticTimeTissuesWorkbasecathepsin Kcellular imagingcofactorcollagenaseenzyme activityfatty acid oxidationfibrotic lunggenetic manipulationhuman diseaseidiopathic pulmonary fibrosisimaging modalityimprovedin vivoinhibitorinsightintravital imaginglung developmentlung repairmouse modelnovelnovel strategiespreventpulmonary functionrepairedresponsetwo photon microscopytwo-photonunpublished works
项目摘要
PROJECT SUMMARY
Idiopathic Pulmonary Fibrosis (IPF) is a rapidly progressing and incurable disease. In healthy tissue, fibroblasts
balance depositing and resorbing extracellular matrix, yet in fibrosis they produce excessive amounts of
extracellular matrix while ECM degrading enzymes are downregulated. Many of these effects may be linked to
a shift in balance to a more oxidative state due to dysregulated metabolism, including inhibition of Cathepsin K,
a collagenolytic enzyme essential to normal lung function and development. Metabolic shifts are known to
increase reactive oxygen species, which themselves alter the overall tissue oxidation-reduction (redox) state.
We believe that to resolve fibrosis, therapeutics should restore the redox balance and repair defective
metabolism. In this project, I will focus on identifying mechanisms regulating the redox state of the fibroblasts
and transitions in this state in vivo during fibrosis and resolution. I will longitudinally monitor Col1a1-GFP+
fibroblasts through a thoracic window and image the autofluorescence of NADH and FAD, two indicators of the
optical redox ratio. Changes to the redox ratio can be indicative of increased ROS. Therefore, by using a thoracic
window to image the cellular redox ratio I can identify changes to the cellular stress in real-time, allowing me to
directly compare changes during fibrosis progression to resolution phases. To further explore the relationship of
fibroblast redox state to fibrosis resolution, I will explore these changes in mouse models of accelerated and
non-resolving fibrosis. I will then mechanistically test the role of PGC1a as a regulator of the redox state in
fibroblasts and will investigate the role the redox ratio plays in regulating Cathepsin K activity as a key link to
fibrosis resolution. I hypothesize that endogenous or exogenous mechanisms that shift the redox state to be
more reductive are essential to restore the fibroblast metabolic state to promote fibrosis resolution. I propose to
test this hypothesis in two specific aims combining intravital imaging, in vitro cell culture, and precision cut lung
slices in combination with selective activation or inhibition of proposed mechanistic pathway components.
Together these combined studies will test the redox ratio as a required regulator of fibrosis resolution.
项目摘要
特发性肺纤维化(IPF)是一种进展迅速且无法治愈的疾病。在健康组织中,成纤维细胞
平衡沉积和再吸收细胞外基质,但在纤维化中它们会产生过量的
细胞外基质,而ECM降解酶下调。其中许多影响可能与
由于代谢失调,包括组织蛋白酶K的抑制,
一种对正常肺功能和发育必不可少的胶原分解酶。众所周知,代谢变化
增加活性氧物质,其本身改变整个组织的氧化-还原(氧化还原)状态。
我们认为,要解决纤维化,治疗应该恢复氧化还原平衡和修复缺陷,
新陈代谢.在这个项目中,我将集中在确定机制调节氧化还原状态的成纤维细胞
以及在纤维化和消退期间在体内这种状态的转变。我将纵向监测Col 1a 1-GFP+
通过胸窗观察成纤维细胞,并对NADH和FAD的自发荧光进行成像,这两种荧光的指标是
光学氧化还原比氧化还原比的变化可以指示增加的ROS。因此,通过使用胸部
我可以实时识别细胞应激的变化,使我能够
直接比较纤维化进展与消退阶段的变化。为了进一步探讨
成纤维细胞氧化还原状态对纤维化的解决,我将探讨这些变化在小鼠模型的加速和
未消退的纤维化然后,我将机械地测试PGC 1a作为氧化还原状态调节剂的作用,
成纤维细胞,并将研究氧化还原比在调节组织蛋白酶K活性中的作用,作为一个关键环节,
纤维化消退。我假设,内源性或外源性机制,改变氧化还原状态,
还原性更强对于恢复成纤维细胞代谢状态以促进纤维化消退是必需的。我建议
在结合活体成像、体外细胞培养和精确切割肺的两个特定目标中测试该假设
切片结合选择性激活或抑制所提出的机制途径组分。
这些联合研究将共同测试氧化还原比作为纤维化消退所需的调节剂。
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 }}
Patrick Link其他文献
Patrick Link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 }}
相似海外基金
University of Aberdeen and Vertebrate Antibodies Limited KTP 23_24 R1
阿伯丁大学和脊椎动物抗体有限公司 KTP 23_24 R1
- 批准号:
10073243 - 财政年份:2024
- 资助金额:
$ 6.76万 - 项目类别:
Knowledge Transfer Partnership
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:
$ 6.76万 - 项目类别:
CAREER: Next-generation protease inhibitor discovery with chemically diversified antibodies
职业:利用化学多样化的抗体发现下一代蛋白酶抑制剂
- 批准号:
2339201 - 财政年份:2024
- 资助金额:
$ 6.76万 - 项目类别:
Continuing Grant
Isolation and characterisation of monoclonal antibodies for the treatment or prevention of antibiotic resistant Acinetobacter baumannii infections
用于治疗或预防抗生素耐药鲍曼不动杆菌感染的单克隆抗体的分离和表征
- 批准号:
MR/Y008693/1 - 财政年份:2024
- 资助金额:
$ 6.76万 - 项目类别:
Research Grant
Discovery of novel nodal antibodies in the central nervous system demyelinating diseases and elucidation of the mechanisms through an optic nerve demyelination model
发现中枢神经系统脱髓鞘疾病中的新型节点抗体并通过视神经脱髓鞘模型阐明其机制
- 批准号:
23K14783 - 财政年份:2023
- 资助金额:
$ 6.76万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Elucidation of the mechanisms controlling the physicochemical properties and functions of supercharged antibodies and development of their applications
阐明控制超电荷抗体的理化性质和功能的机制及其应用开发
- 批准号:
23KJ0394 - 财政年份:2023
- 资助金额:
$ 6.76万 - 项目类别:
Grant-in-Aid for JSPS Fellows
Developing first-in-class aggregation-specific antibodies for a severe genetic neurological disease
开发针对严重遗传神经系统疾病的一流聚集特异性抗体
- 批准号:
10076445 - 财政年份:2023
- 资助金额:
$ 6.76万 - 项目类别:
Grant for R&D
PLA2G2D Antibodies for Cancer Immunotherapy
用于癌症免疫治疗的 PLA2G2D 抗体
- 批准号:
10699504 - 财政年份:2023
- 资助金额:
$ 6.76万 - 项目类别:
Genetic adjuvants to elicit neutralizing antibodies against HIV
基因佐剂可引发抗艾滋病毒中和抗体
- 批准号:
10491642 - 财政年份:2023
- 资助金额:
$ 6.76万 - 项目类别:
Novel Immunogens to Elicit Broadly Cross-reactive Antibodies That Target the Hemagglutinin Head Trimer Interface
新型免疫原可引发针对血凝素头三聚体界面的广泛交叉反应抗体
- 批准号:
10782567 - 财政年份:2023
- 资助金额:
$ 6.76万 - 项目类别: