Targeting pathologic G-protein signaling in cardiac and kidney fibrosis
靶向心脏和肾脏纤维化中的病理性 G 蛋白信号传导
基本信息
- 批准号:9169956
- 负责人:
- 金额:$ 48.36万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-09-01 至 2020-07-31
- 项目状态:已结题
- 来源:
- 关键词:AblationAcuteAddressAgonistAttenuatedBiological AssayBreedingCardiacCardiac MyocytesCardiovascular DiseasesCardiovascular PathologyCellsCharacteristicsChronicDepositionDiseaseDisease ProgressionEndothelinEndothelin-2Epithelial CellsExtracellular MatrixFDA approvedFailureFibroblastsFibrosisFunctional disorderG protein coupled receptor kinaseG-Protein-Coupled ReceptorsGTP-Binding ProteinsGeneticHeartHeart failureHumanInjuryIschemiaKidneyKidney FailureKnock-in MouseKnockout MiceLeadMechanicsMediator of activation proteinMembraneMolecularMusMyocardial IschemiaMyocardial dysfunctionMyofibroblastOrganOutcomePathologicPatientsPericytesPhosphotransferasesPlayPublic HealthReagentRecruitment ActivityRenal functionReperfusion InjuryReperfusion TherapyRodentRoleSignal TransductionSpecificitySyndromeTherapeuticTissuesTreatment EfficacyUnited StatesUp-RegulationVentricularbaseconstrictioncoronary fibrosisgalleinin vivoinhibitor/antagonistinterstitialmortalitymouse modelnew therapeutic targetnoveloutcome forecastprotective effectrenal ischemiaresponsesmall moleculetargeted treatmenttherapeutic target
项目摘要
Summary: Fibrosis is a key component of pathologic remodeling in multiple tissues, no therapies specifically
target maladaptive fibrosis. Heart failure (HF), the final manifestation of many cardiovascular pathologies, is a
devastating disease with poor prognosis, exacerbated by concomitant kidney dysfunction. Cardiorenal
syndrome (CRS) is the pathologic crosstalk between the heart and kidney, including increased fibrosis and
failure of both organsd. Worsening renal function co-exists with HF in CRS2 and is a strong predictor of
mortality in HF patients. Pathologically activated fibroblasts transition to myofibroblasts (MFs) to exacerbate
tissue remodeling. Novel POSTNMerCreMer and Tcf21MerCreMer knock-in mice permit targeted, inducible fibroblast
modulation in vivo. In HF or kidney injury, chronic stimulation of G-protein coupled receptors (GPCRs) elicits
pathologic upregulation of GPCR kinase 2 (GRK2) that is recruited to membrane Gβγ subunits to modulate
agonist-occupied GPCRs. Systemic delivery of our novel small molecule Gβγ-GRK2 inhibitor, gallein,
attenuates fibrosis, HF and GRK2 expression following transverse aortic constriction (TAC). GRK2 ablation in
activated fibroblasts (GRK2fl/fl-POSTNMerCreMer) after cardiac ischemia/reperfusion (I/R) injury was
cardioprotective, with no further protection conferred by gallein. TAC or I/R injury resulted in CRS2, including
kidney fibrosis and dysfunction, as well as elevation of GRK2 and endothelin (ET) characteristic of renal
dysfunction. Gallein attenuated kidney fibrosis, dysfunction, GRK2 expression and ET following TAC or I/R.
Gβγ-GRK2 inhibition also attenuated renal dysfunction and fibrosis following acute renal I/R injury, suggesting
a direct protective effect of blocking Gβγ-GRK2 signaling in kidney dysfunction. Novel Cre mice ablate GRK2
in either kidney pericytes (FoxD1Cre) or epithelial cells (Six2Cre) and will be used to evaluate the role of Gβγ-
GRK2 signaling in kidney fibrosis. Our hypothesis is that Gβγ-GRK2 plays an important role in pathologic
fibrotic remodeling in both HF progression and kidney dysfunction and that its inhibition holds
therapeutic promise for fibrotic remodeling in HF, kidney injury and CRS2. To address our hypothesis,
we propose the following: Aim 1. Determine the therapeutic efficacy and specificity of Gβγ-GRK2
inhibition or ablation in cardiac fibrosis and CRS2. Aim 2. Determine the therapeutic efficacy and
specificity of Gβγ-GRK2 inhibition or ablation in renal fibrosis and CRS2. Specific Aim 3: Elucidate the
cellular mechanisms of Gβγ-GRK2 inhibition in cardiac and renal fibroblasts and validate Gβγ-GRK2 as
a therapeutic target in mouse and human cardiac fibrosis, kidney fibrosis and HF. We believe this
proposal, with Gβγ-GRK2 inhibitory compounds validated in various GRK2 null mice in cardiac and renal
fibrosis, holds therapeutic promise for HF, CRS2, kidney injury and possibly other fibrotic diseases.
摘要:纤维化是多种组织病理性重塑的重要组成部分,目前尚无特效治疗方法。
以适应不良纤维化为目标。心力衰竭(HF)是许多心血管疾病的最终表现,是一种
严重的疾病,预后不佳,因伴有肾功能障碍而加重。心肾
综合征(CRS)是心脏和肾脏之间的病理串扰,包括增加的纤维化和
两个组织都失败了。CRS2患者肾功能恶化与心力衰竭并存,是一个强有力的预测因素
心力衰竭患者的死亡率。病理激活的成纤维细胞转化为肌成纤维细胞(MFS)以加重
组织重塑。新型POSTNMerCreMer和Tcf21MerCreMer敲入鼠允许靶向、可诱导的成纤维细胞
体内的调制。在心力衰竭或肾脏损伤中,G蛋白偶联受体(GPCRs)的慢性刺激引起
膜G-βγ亚基参与调节的GRK2的病理性上调
激动剂占据的GPCRs。我们的新型小分子Gβγ-GRK2抑制剂Gallein,
减轻横断性主动脉缩窄(TAC)后的纤维化、HF和GRK2的表达。GRK2消融
心肌缺血再灌注损伤后活化的成纤维细胞(GRK2fl/fl-POSTNMerCreMer)
心脏保护,没有由帆船提供的进一步保护。TAC或I/R损伤导致CRS2,包括
肾脏纤维化和功能障碍以及肾脏GRK2和内皮素(ET)的升高
功能障碍。帆船可减轻TAC或I/R后肾纤维化、肾功能障碍、GRK2表达和ET。
抑制Gβγ-GRK2也可减轻急性肾I/R损伤后的肾功能障碍和纤维化,提示
阻断G-βγ-GRK2信号通路对肾功能不全的直接保护作用新型CRE小鼠消融GRK2
在肾周细胞(FoxD1Cre)或上皮细胞(Six2Cre)中的表达,并将用于评估Gβγ-
GRK2信号在肾纤维化中的作用我们的假设是G-βγ-GRK2在病理过程中起重要作用
纤维化重塑在心力衰竭进展和肾功能障碍中的作用及其抑制作用
心衰、肾损伤和CRS2纤维化重塑的治疗前景。为了解释我们的假设,
我们提出如下建议:目的1.确定Gβγ-GRK2的治疗效果和特异性
抑制或消融心脏纤维化和CRS2。目的2.确定治疗效果和
G-βγ-GRK2抑制或消融在肾纤维化和CRS2中的特异性。具体目标3:阐明
G-βγ-GRK2抑制心脏和肾脏成纤维细胞的细胞机制及验证G-βγ-GRK2作为
治疗小鼠和人类心脏纤维化、肾纤维化和心衰的靶点。我们相信这一点
GRK2-GRK2抑制化合物在不同βγ基因缺失的小鼠心脏和肾脏中的验证
纤维化,对心力衰竭、CRS2、肾脏损伤以及可能的其他纤维化疾病具有治疗前景。
项目成果
期刊论文数量(0)
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会议论文数量(0)
专利数量(0)
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Burns C Blaxall其他文献
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{{ truncateString('Burns C Blaxall', 18)}}的其他基金
Targeting Gbg-GRK2 signaling in fibrotic remodeling
纤维化重塑中靶向 Gbg-GRK2 信号传导
- 批准号:
9125578 - 财政年份:2016
- 资助金额:
$ 48.36万 - 项目类别:
Targeting Gbg-GRK2 signaling in fibrotic remodeling
纤维化重塑中靶向 Gbg-GRK2 信号传导
- 批准号:
9233187 - 财政年份:2016
- 资助金额:
$ 48.36万 - 项目类别:
Targeting pathologic G-protein signaling in cardiac and kidney fibrosis
靶向心脏和肾脏纤维化中的病理性 G 蛋白信号传导
- 批准号:
9340263 - 财政年份:2016
- 资助金额:
$ 48.36万 - 项目类别:
Small molecule targeting of MLK3 for heart failure
MLK3 小分子靶向治疗心力衰竭
- 批准号:
9053110 - 财政年份:2015
- 资助金额:
$ 48.36万 - 项目类别:
Targeting of B-AR/GBy signaling in the heart with small molecules
用小分子靶向心脏中的 B-AR/GBy 信号传导
- 批准号:
8056631 - 财政年份:2010
- 资助金额:
$ 48.36万 - 项目类别:
Targeting of B-AR/GBy signaling in the heart with small molecules
用小分子靶向心脏中的 B-AR/GBy 信号传导
- 批准号:
7890141 - 财政年份:2010
- 资助金额:
$ 48.36万 - 项目类别:
Targeting of B-AR/GBy signaling in the heart with small molecules
用小分子靶向心脏中的 B-AR/GBy 信号传导
- 批准号:
8235833 - 财政年份:2010
- 资助金额:
$ 48.36万 - 项目类别:
Targeting of B-AR/GBy signaling in the heart with small molecules
用小分子靶向心脏中的 B-AR/GBy 信号传导
- 批准号:
8450792 - 财政年份:2010
- 资助金额:
$ 48.36万 - 项目类别:
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