Novel downstream effectors of protein kinase G in hypertensive disease
高血压疾病中蛋白激酶 G 的新型下游效应子
基本信息
- 批准号:10228381
- 负责人:
- 金额:$ 62.22万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-04-01 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAgingAmericanAnimal ModelAortic Valve StenosisBiological AvailabilityBypassCardiacCardiovascular systemChronicChronic stressClinicalClinical TrialsComplexConsciousCyclic AMP-Dependent Protein KinasesCyclic GMP-Dependent Protein KinasesDeath RateDependovirusDevelopmentDiseaseEFRACEconomic BurdenExperimental ModelsFailureFoundationsFunctional disorderGene DeliveryGene TransferGenerationsGenetically Engineered MouseGenomicsHeartHeart failureHypertensionImpairmentIn VitroIncidenceIndividualKidneyLeftLeft Ventricular DysfunctionMeasurementMeasuresMedicalModelingMolecularMorbidity - disease rateMusMuscleMutationMyocardial dysfunctionMyocardiumNephronsNitric OxideOrganOutcomeOxidative StressPathologicPatientsPhenotypePhosphorylationPrevalencePreventionPrognosisPropertyReactive Oxygen SpeciesRegulationRelaxationRenal functionResistanceRiskRisk FactorsSerineSignal PathwaySignal TransductionSodiumStressTestingTransgenic AnimalsTransgenic MiceUnited StatesVentricularVentricular Remodelingagedblood pressure reductioncGMP-dependent protein kinase Icardiogenesiscardioprotectioncardiovascular risk factorconventional therapydesigneffective therapygenetic regulatory proteinhealth economicsheart functionhuman old age (65+)improvedimproved outcomein vivokidney dysfunctionmortalitynew therapeutic targetnormotensivenovelnovel therapeutic interventionnovel therapeuticsolder patientpreservationpressurepreventrenal damageresponseside effectsocioeconomicssuccesssystemic inflammatory responsetherapy developmenttooltranslational studyviral gene delivery
项目摘要
Abstract
Hypertension is an enormous health and socio-economic burden in the United States and is a leading cause of
cardiovascular morbidity and mortality worldwide. Overall, 1 in 3 of Americans have hypertension, and nearly 2
in 3 of Americans over the age of 65 years. Hypertension significantly increases the risk of developing heart
failure (HF), whereas reducing blood pressure decreases the risk. It is known that hypertension is the most
common risk factor in the development of HF with preserved ejection fraction (HFpEF) by a mechanism where
systemic inflammation and activation of reactive oxygen species reduces nitric oxide bioavailability and impairs
Protein kinase G (PKG) signaling. Chronic hypertension is characterized by impaired systolic and diastolic
cardiac function and pathological remodeling, and excessive renal sodium retention and volume overload, which
together contribute to progression to HFpEF and a poor prognosis. Therapies attempting to reduce blood
pressure in HFpEF patients have mostly failed to yield positive results. Many patients have hypertension that is
resistant to conventional therapy, and because the majority of HFpEF patients are elderly, they display aging
inherent deficits in nitric oxide bioavailability and PKG signaling that make available therapies less effective.
Although, it is known that impaired PKG signaling is central to the cardio-renal deficits related to hypertension
especially in older individuals, therapies specifically designed to enhance PKG activity have not been successful.
Our preliminary studies have explored an alternative approach to manipulating PKG levels to improve outcomes
in hypertension and HFpEF by bypassing complex signaling cascades in favor of directly targeting the
downstream effectors of PKG. We have identified a phosphorylatable serine residue 273 (S273) in the regulatory
protein MyBPC as a critical specific downstream target of PKG that is upregulated in various models of pressure
overload-induced hypertension, but is downregulated in models of HFpEF. These observations lay the
foundation for our general hypothesis that increasing S273 phosphorylation levels in chronic Htn prevents
progression to HFpEF. In Aim 1 we will define the PKG-specific in vitro molecular mechanisms of S273
phosphorylation, in Aim 2 we will utilize experimental models of hypertension and HFpEF and novel transgenic
animal models to determine the in vivo functional consequences of altered PKG levels and aging, and in Aim 3
we will utilize in vivo cardioselective AAV9 viral gene delivery of phosphomimetic S273 to prevent or reverse the
HFpEF phenotype in aged mice and in mice with ablated PKG. Successful completion of these mechanistic
studies have the promise to identify S273 as a novel therapeutic strategy to treat hypertension-induced HFpEF,
a devastating disease with no effective treatments.
摘要
高血压在美国是一个巨大的健康和社会经济负担,并且是高血压的主要原因。
全球心血管疾病发病率和死亡率。总的来说,三分之一的美国人患有高血压,
在65岁以上的美国人中,高血压会显著增加心脏病的风险
心力衰竭(HF),而降低血压可降低风险。据了解,高血压是最
射血分数保留性心力衰竭(HFpEF)发展的常见风险因素,其机制是
全身性炎症和活性氧的活化降低了一氧化氮的生物利用度,
蛋白激酶G(PKG)信号传导。慢性高血压的特征是收缩和舒张功能受损
心功能和病理性重塑,以及过度的肾钠潴留和容量超负荷,
共同导致进展为HFpEF和预后不良。试图减少血液的治疗
HFpEF患者的压力大多未能产生阳性结果。许多患者患有高血压,
对常规治疗有抵抗力,并且由于大多数HFpEF患者是老年人,
一氧化氮生物利用度和PKG信号传导的固有缺陷使得可用的疗法不太有效。
虽然,已知PKG信号传导受损是与高血压相关的心肾缺陷的中心
特别是在老年人中,专门设计用于增强PKG活性的疗法尚未成功。
我们的初步研究探索了一种替代方法来操纵PKG水平,以改善结果
在高血压和HFpEF中,通过绕过复杂的信号级联,有利于直接靶向
PKG的下游效应子。我们已经确定了一个磷酸化的丝氨酸残基273(S273)的调节
蛋白MyBPC作为PKG的关键特异性下游靶点,在各种压力模型中上调
超负荷诱导的高血压,但在HFpEF模型中下调。这些观察奠定了
这为我们的一般假设奠定了基础,即在慢性HTN中增加S273磷酸化水平可以防止
进展为HFpEF。在目的1中,我们将定义S273的PKG特异性体外分子机制
在目标2中,我们将利用高血压和HFpEF的实验模型和新的转基因动物。
动物模型,以确定改变的PKG水平和衰老的体内功能后果,目的3
我们将利用体内心脏选择性AAV9病毒基因递送磷酸化模拟物S273来预防或逆转心肌缺血。
老年小鼠和消融PKG小鼠中的HFpEF表型。成功完成这些机械化
研究有希望鉴定S273作为治疗高血压诱导的HFpEF的新治疗策略,
一种无法有效治疗的毁灭性疾病
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)
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Julian Stelzer其他文献
Julian Stelzer的其他文献
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{{ truncateString('Julian Stelzer', 18)}}的其他基金
Novel downstream effectors of protein kinase G in hypertensive disease
高血压疾病中蛋白激酶 G 的新型下游效应子
- 批准号:
10593096 - 财政年份:2021
- 资助金额:
$ 62.22万 - 项目类别:
Novel downstream effectors of protein kinase G in hypertensive disease
高血压疾病中蛋白激酶 G 的新型下游效应子
- 批准号:
10380140 - 财政年份:2021
- 资助金额:
$ 62.22万 - 项目类别:
High resolution ultrasound for small animal imaging
用于小动物成像的高分辨率超声
- 批准号:
9075609 - 财政年份:2016
- 资助金额:
$ 62.22万 - 项目类别:
Functional consequences of FHC mutations in cardiac MyBPC
心脏 MyBPC 中 FHC 突变的功能后果
- 批准号:
9206516 - 财政年份:2013
- 资助金额:
$ 62.22万 - 项目类别:
Functional consequences of FHC mutations in cardiac MyBPC
心脏 MyBPC 中 FHC 突变的功能后果
- 批准号:
8606772 - 财政年份:2013
- 资助金额:
$ 62.22万 - 项目类别:
Functional consequences of FHC mutations in cardiac MyBPC
心脏 MyBPC 中 FHC 突变的功能后果
- 批准号:
8795220 - 财政年份:2013
- 资助金额:
$ 62.22万 - 项目类别:
Functional consequences of FHC mutations in cardiac MyBPC
心脏 MyBPC 中 FHC 突变的功能后果
- 批准号:
10602552 - 财政年份:2013
- 资助金额:
$ 62.22万 - 项目类别:
Functional consequences of FHC mutations in cardiac MyBPC
心脏 MyBPC 中 FHC 突变的功能后果
- 批准号:
10222750 - 财政年份:2013
- 资助金额:
$ 62.22万 - 项目类别:
Functional consequences of FHC mutations in cardiac MyBPC
心脏 MyBPC 中 FHC 突变的功能后果
- 批准号:
9973440 - 财政年份:2013
- 资助金额:
$ 62.22万 - 项目类别:
Functional consequences of FHC mutations in cardiac MyBPC
心脏 MyBPC 中 FHC 突变的功能后果
- 批准号:
10379420 - 财政年份:2013
- 资助金额:
$ 62.22万 - 项目类别:
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