Role of Fgfr2 signaling in bladder injury and regeneration
Fgfr2信号在膀胱损伤和再生中的作用
基本信息
- 批准号:10187557
- 负责人:
- 金额:$ 22.93万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-07-16 至 2022-06-30
- 项目状态:已结题
- 来源:
- 关键词:AffectAftercareAnimalsApoptosisApoptoticAttenuatedAutomobile DrivingBasal CellBiological AssayBladderBladder InjuryBladder Urothelial CellBladder UrotheliumCell Culture TechniquesCell CycleCell NucleusCellsChemicalsCyclophosphamideCystitisCytoprotectionDNA DamageDNA Replication DamageDNA biosynthesisDataDefectDepressed moodEnzymesEpithelialFibroblast Growth FactorFibroblast Growth Factor Receptor 2GeneticGoalsHealthHemorrhageHistologyHourHumanHyperplasiaInflammationInfusion proceduresInjectionsInjuryKeratinLeadLifeLigandsMalignant neoplasm of urinary bladderMediatingMitosisMolecularMolecular TargetMusMutant Strains MiceNatural regenerationNecrosisNonpenetrating WoundsPathologicPatientsPharmaceutical PreparationsPlayPloidiesPolyploidyProteinsRecombinantsResolutionRoleSignal TransductionStainsStratum BasaleTestingTherapeuticTissuesTransducersUrothelial CellUrothelial HyperplasiaUrotheliumWild Type Mousebasecell injurycell typechemotherapydruggable targetepithelial injuryinhibitor/antagonistkeratinocyte growth factormutantpreservationpreventprotective effectrepairedreplication stressresponserestorationstem cellstherapeutic targeturothelial injury
项目摘要
Project Summary/Abstract:
Cyclophosphamide (CPP)-induced injury to bladder urothelium can lead to life-threatening health conditions
including hemorrhagic cystitis and bladder cancer. The application’s broad long-term objectives are to identify
mechanisms driving CPP bladder injury and thus therapeutic targets. CPP induces urothelial loss from apoptosis
and necrosis within 48 hours, followed by proliferation and repair finishing by 14 days. While fibroblast growth
factor receptor 2 (Fgfr2) activity blunts injury in other tissues, roles of Fgfr2 in CPP-induced urothelial injury are
unclear. Preliminary data shows that Fgfr2: 1) dampens urothelial cell loss and 2) enhances urothelial repair
after CPP injury. Regarding cell loss, injection of keratinocyte growth factor (KGF), a ligand for epithelial Fgfr2,
24 hours prior to CPP in wildtype mice blocks apoptotic urothelial cell loss. Akt, a transducer of Fgf signaling and
known repressor of apoptosis, is upregulated in urothelium after KGF. Regarding regeneration, mice with
conditional deletion of Fgfr2 in all bladder urothelial layers have defective urothelial repair after injury. At 3 days
post-CPP, controls had urothelial hyperplasia, significant restoration of uroplakin (barrier protein) staining and
major resolution of inflammation and hemorrhage, while mutant bladders had less hyperplasia, attenuated
uroplakin staining, and ongoing hemorrhage and inflammation. While both mutants and controls had expansion
of Keratin 14 (Krt14)-positive putative progenitor cells across basal layers 3 days after CPP, mutant Krt14+ cells
were hypertrophic with enlarged nuclei suggesting a cell cycle defect. Cell cycle profiling and assays for DNA
content suggest that mutant Krt14+ cells have aberrant endoreplication (DNA replication without completion of
mitosis, leading to polyploidy). Fgfr2-mutant cells undergoing apparent endoreplication also had evidence of
increased DNA damage/replication stress 3 days after injury. Given that Fgfr2 stimulates Erk that can suppress
cell cycle entry and endoreplication, Erk and its readouts were assessed and both were reduced in mutants 3
days after CPP. Regeneration defects, including large (likely polyploid) Krt14+ cells, persisted 10 days after CPP.
Together, the hypothesis is that Fgfr2 signaling ameliorates urothelial injury from CPP by suppressing apoptosis
via Akt and promotes regeneration after CPP by repressing endoreplication of urothelium via Erk. To test this
hypothesis, the following Aims are proposed: Aim 1: Investigate how stimulation of Fgfr2 signaling blocks CPP-
induced bladder urothelial cell loss. Whole animal and cell-based assays will elucidate roles of Fgfr2/Akt to block
CPP-induced apoptotic injury. Akt inhibitors will be used prior to KGF to show roles of Akt downstream of Fgfr2.
Aim 2: Determine how Fgfr2 promotes regeneration of bladder urothelium after CPP-injury. Whole animal and
cell-based assays will elucidate roles of Fgfr2/Erk to suppress endoreplication and drive regeneration, including
genetic rescue with constitutively active Erk in mutants and chemical rescue to accelerate repair in controls. Aim
3: Identify the cell-specific roles of Fgfr2 signaling in the bladder urothelium after CPP injury. Fgfr2 will be deleted
in specific urothelial layers to identify cell-specific actions after CPP-injury.
项目概要/摘要:
环磷酰胺(CPP)诱导的膀胱尿道损伤可导致危及生命的健康状况
包括出血性膀胱炎和膀胱癌。该应用程序的广泛的长期目标是确定
驱动CPP膀胱损伤的机制和因此的治疗靶点。CPP诱导尿路上皮细胞凋亡
48 h内坏死,14 d后增殖修复完成。当成纤维细胞生长
因子受体2(Fgfr 2)活性减弱其他组织的损伤,Fgfr 2在CPP诱导的尿路上皮损伤中的作用是
不清楚初步数据显示,Fgfr 2:1)抑制尿路上皮细胞损失和2)增强尿路上皮修复
CPP损伤后关于细胞损失,注射角质形成细胞生长因子(KGF),一种上皮Fgfr 2的配体,
在野生型小鼠中,CPP前24小时阻断凋亡性尿路上皮细胞损失。Akt,一种FGF信号传导的转换器,
已知的细胞凋亡阻遏物在KGF之后的尿路上皮中上调。关于再生,
所有膀胱尿路上皮层中Fgfr 2的条件性缺失在损伤后具有缺陷的尿路上皮修复。3天
CPP后,对照组有尿路上皮增生,尿斑蛋白(屏障蛋白)染色显著恢复,
炎症和出血的主要解决,而突变膀胱的增生较少,
尿斑蛋白染色和持续出血和炎症。而突变体和对照组都有扩增,
CPP后3天,角蛋白14(Krt 14)阳性推定祖细胞穿过基底层,突变Krt 14+细胞
肥大细胞核增大提示细胞周期缺陷。细胞周期分析和DNA测定
内容表明突变Krt 14+细胞具有异常的核内复制(DNA复制没有完成,
有丝分裂,导致多倍体)。经历明显的内复制的Fgfr 2突变细胞也有证据表明,
损伤后3天DNA损伤/复制应激增加。鉴于Fgfr 2刺激Erk,
细胞周期进入和内复制,Erk及其读数进行了评估,两者都减少突变体3
CPP后的几天再生缺陷,包括大(可能是多倍体)Krt 14+细胞,持续10天后CPP。
总之,假设Fgfr 2信号通过抑制细胞凋亡来改善CPP引起的尿路上皮损伤
并通过Erk抑制尿激酶的内复制促进CPP后的再生。为了验证这一
假设,提出了以下目的:目的1:研究Fgfr 2信号转导的刺激如何阻断CPP。
诱导膀胱尿路上皮细胞丢失。全动物和基于细胞的测定将阐明Fgfr 2/Akt阻断
CPP诱导的凋亡性损伤。Akt抑制剂将在KGF之前使用,以显示Akt在Fgfr 2下游的作用。
目的2:确定Fgfr 2如何促进CPP损伤后膀胱尿道的再生。整个动物和
基于细胞的分析将阐明Fgfr 2/Erk抑制核内复制和驱动再生的作用,包括
在突变体中用组成型活性Erk进行遗传拯救,在对照中用化学拯救加速修复。目的
3:确定CPP损伤后Fgfr 2信号传导在膀胱尿道炎中的细胞特异性作用。Fgfr 2将被删除
在特定的尿路上皮层,以确定CPP损伤后的细胞特异性行动。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Role of ERK signaling in bladder urothelium in response to cyclophosphamide injury.
- DOI:10.14814/phy2.15378
- 发表时间:2022-07
- 期刊:
- 影响因子:2.5
- 作者:
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CARLTON MATTHEW BATES其他文献
CARLTON MATTHEW BATES的其他文献
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{{ truncateString('CARLTON MATTHEW BATES', 18)}}的其他基金
The University of Pittsburgh Summer Research Internship Program kidney workshop (SRIP-Kid)
匹兹堡大学夏季研究实习计划肾脏研讨会(SRIP-Kid)
- 批准号:
10088062 - 财政年份:2021
- 资助金额:
$ 22.93万 - 项目类别:
Role of Fgfr2 signaling in bladder injury and regeneration
Fgfr2信号在膀胱损伤和再生中的作用
- 批准号:
9978050 - 财政年份:2019
- 资助金额:
$ 22.93万 - 项目类别:
Critical Roles for Fibroblast Growth Factor Receptors in Bladder Development
成纤维细胞生长因子受体在膀胱发育中的关键作用
- 批准号:
8985305 - 财政年份:2015
- 资助金额:
$ 22.93万 - 项目类别:
The 13th International Workshop on Developmental Nephrology: From Basic Models to Translational Science
第十三届发育肾病学国际研讨会:从基础模型到转化科学
- 批准号:
8908658 - 财政年份:2015
- 资助金额:
$ 22.93万 - 项目类别:
12th International Workshop on Developmental Nephrology
第十二届发育肾病学国际研讨会
- 批准号:
8517912 - 财政年份:2013
- 资助金额:
$ 22.93万 - 项目类别:
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