Central GRK5 modulation of Angiotensin II receptor expression in heart failure
GRK5 对心力衰竭中血管紧张素 II 受体表达的中枢调节
基本信息
- 批准号:8397394
- 负责人:
- 金额:$ 5.22万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-07-01 至 2015-06-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAnesthesia proceduresAngiotensin IIAngiotensin II ReceptorAnimal ModelAnimalsAttenuatedBaroreflexBrainBrain StemBrain regionCardiacCause of DeathCell LineCellsChronicComplexCoronary arteryDataDiagnosisDiseaseDissociationDominant-Negative MutationEchocardiographyExcretory functionExerciseFrequenciesG protein coupled receptor kinaseG-Protein-Coupled ReceptorsGRKGRK5 geneGenetic TranscriptionHeart RateHeart failureHypertensionHypothalamic structureIn VitroInjection of therapeutic agentLaboratoriesLeadLigationLinkMeasuresMediatingMusMuscleNerveNeuronsNorepinephrineNuclearPatientsPhosphorylationPhosphotransferasesPlasmaPlasmidsPlayProcessQuality of lifeRattusReceptor, Angiotensin, Type 1RecyclingRegulationRoleSmall Interfering RNASubfamily lentivirinaeTechniquesTestingTherapeuticTrainingTranscriptional RegulationUbiquitin-Proteasomal PathwayUnited StatesUp-Regulationeffective therapyhemodynamicsimprovedindexingoverexpressionparaventricular nucleuspressurepreventprotein expressionreceptorreceptor expressionreceptor upregulationresearch studyresponsesedentarytherapeutic developmenttherapeutic targeturinary
项目摘要
DESCRIPTION (provided by applicant): This proposal will address the following specific aims: (1) Determine the role(s) of central GRK5 in the regulation of AT1R (Angiotensin II type 1 Receptor) expression under normal conditions and during Chronic Heart Failure (CHF). (2) Identify the mechanism(s) of modulation of central AT1R and GRK5 following Exercise Training (ExT) in CHF animals. (3) Determine the role of cytosolic and nuclear GRK5 in the transcriptional regulation of AT1R by I?B¿ and NF-?B. In Specific Aim 1 we will induce CHF by coronary artery ligation. Overexpression of GRK5 will be targeted to the RVLM or PVN by lentiviral injection. To determine the effects of GRK5 knockdown on AT1R expression and changes in sympatho-excitation, we will utilize both commercially available GRK5 KO mice and lentiviral packaged siRNA against GRK5 that will be injected into the RVLM or PVN. Urinary excretion of norepinephrine (NE), plasma NE and Ang II will be measured in all animal groups. Arterial pressure and heart rate will be continuously recorded in order to derive additional indices of sympatho-excitation and to determine arterial baroreflex function. Sympathetic nerve activity will be directly recorded under anesthesia in terminal experiments. In all animals cardiac
function will be evaluated serially by high-frequency echocardiography. In Specific Aim 2, we will induce CHF in GRK5KO mice that are either sedentary or ExT as well as utilize CHF rats in which GRK5 has been silenced in the PVN or RVLM using siRNA lentivirus. Following ExT, sympathetic and baroreflex function will be evaluated in a similar fashion as in Specific Aim 1. We will test Specific Aim 3 in CATH.a neurons, utilizing both overexpression and silencing techniques with a GRK5 plasmid and siRNA to examine the subcellular localization of AT1R, I?B¿, NF-?B, and GRK5 following Ang II stimulation. We will also perform parallel studies using a K215R dominant negative GRK5 construct to determine if the GRK5/AT1R/I?B¿/NF-?B interaction is kinase-dependent.
PUBLIC HEALTH RELEVANCE: Chronic Heart Failure (CHF) is one of the leading causes of death in the United States (600,000 new diagnoses each year), and is characterized in part by increased sympathetic nerve activity mediated in part by upregulation of the Angiotensin II type 1 Receptor (AT1R). Exercise training is an accepted therapy in patients with CHF and can increase survival, decrease complications, and abrogate increases in muscle sympathetic nerve activity. Gaining a greater understanding of the regulation of AT1R both during CHF and following ExT may lead to development of therapeutics and more effective treatment of this disease.
描述(申请人提供):这项建议将针对以下具体目标:(1)确定中央GRK5在正常情况下和慢性心力衰竭(CHF)期间调节AT1R(血管紧张素II 1型受体)表达中的作用(S)。(2)明确运动训练(EXT)后CHF动物中枢AT1R和GRK5的调节机制(S)。(3)确定胞浆和胞核GRK5在I?B和NF-?B对AT1R转录调控中的作用。GRK5的过表达将通过慢病毒注射靶向RVLM或PVN。为了确定GRK5基因敲除对AT1R表达和交感兴奋变化的影响,我们将利用商用的GRK5 KO小鼠和慢病毒包装的针对GRK5的siRNA,并将其注射到RVLM或PVN中。测定所有动物组尿去甲肾上腺素(NE)、血浆去甲肾上腺素(NE)和血管紧张素Ⅱ(Ang II)的排泄量。将连续记录动脉压和心率,以得出交感神经兴奋的额外指标,并确定动脉压力感受器反射功能。在终末实验中,将在麻醉下直接记录交感神经活动。在所有动物的心脏中
功能将通过高频超声心动图进行连续评估。在具体目标2中,我们将在久坐或EXT状态的GRK5KO小鼠中诱导CHF,并利用GRK5在PVN或RVLM中使用siRNA慢病毒沉默的CHF大鼠。在EXT之后,交感和压力感受性反射功能的评估将以与特定目标1类似的方式进行。我们将测试特定目标3在CATH.a神经元中的作用,利用GRK5质粒和siRNA的过度表达和沉默技术来检测Ang II刺激后AT1R、I?B、NF-?B和GRK5的亚细胞定位。我们还将使用K215R显性负GRK5结构进行平行研究,以确定GRK5/AT1R/I?B/NF-?B相互作用是否依赖于激酶。
公共卫生相关性:慢性心力衰竭(CHF)是美国主要的死亡原因之一(每年新增60万例诊断),其部分特征是交感神经活动增加,部分是由血管紧张素II 1型受体(AT1R)上调介导的。运动训练是CHF患者公认的治疗方法,可以提高存活率,减少并发症,消除肌交感神经活动的增加。更好地了解AT1R在CHF期间和EXT后的调节可能会导致治疗方法的发展和对这种疾病的更有效的治疗。
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)
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Karla Haack其他文献
Karla Haack的其他文献
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{{ truncateString('Karla Haack', 18)}}的其他基金
Central GRK5 modulation of Angiotensin II receptor expression in heart failure
GRK5 对心力衰竭中血管紧张素 II 受体表达的中枢调节
- 批准号:
8531707 - 财政年份:2012
- 资助金额:
$ 5.22万 - 项目类别: