Neurovascular Regulation During Exercise in Humans With Chronic Kidney Disease
慢性肾病患者运动期间的神经血管调节
基本信息
- 批准号:10669257
- 负责人:
- 金额:$ 69.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-01-01 至 2027-06-30
- 项目状态:未结题
- 来源:
- 关键词:ASIC channelAcidosisAcidsActivities of Daily LivingAcuteAdultAerobic ExerciseAffectBicarbonatesBiological AvailabilityBiological MarkersBlood PressureBuffersCardiovascular systemChronic Kidney FailureClinicalCombined Modality TherapyDiseaseEventExcretory functionExerciseFundingGene ExpressionGenerationsGoalsHumanHypertensionImaging TechniquesImpairmentIndividualInflammationIntravenous infusion proceduresIschemiaIsometric ExerciseIsotonic ExerciseKidneyKidney DiseasesKneeMagnetic Resonance ImagingMagnetic Resonance SpectroscopyMeasuresMediatingMetabolic acidosisMethodsMuscleNear-Infrared SpectroscopyNerveNerve EndingsOralOutcomePatientsPeriodicityPhysical CapacityPhysical FunctionPhysical activityPhysiologicalPlacebosPlayPopulationQuality of lifeRandomizedRecommendationReflex actionRegulationRenal functionResearchRestRiskRoleSerumSpinal GangliaSudden DeathSupplementationSympathetic Nervous SystemTestingTranslatingTranslational ResearchWorkafferent nerveblood pressure elevationcardiovascular risk factorclinical practiceexercise capacityexercise intoleranceexercise traininghemodynamicshigh riskimprovedinnovationinsightinterstitiallean body massmortalityneuralneurovascularnovel therapeutic interventionpatient populationpreventprimary outcomeprogramsprotein expressionreceptorrehabilitation strategyresponserestorationsecondary outcomesystemic inflammatory responsetherapeutic targettreatment guidelines
项目摘要
~37 million (or 15% of US adults) have chronic kidney disease (CKD) and are at profoundly increased
risk of cardiovascular mortality by virtue of having reduced renal function. CKD patients have exaggerated
increases in blood pressure (BP) during physical activity that contributes to increased cardiovascular risk and
poor physical capacity. Our prior work has demonstrated that this augmented pressor response in CKD is due
to exaggerated increases in reflex activation of the sympathetic nervous system (SNS) during exercise that is
mediated by muscle afferent nerve activation, referred to as the exercise pressor reflex. Importantly, such
heightened SNS and pressor responses contribute to increased risk of adverse cardiovascular events,
including sudden death, during physical activity, as well as exercise intolerance that has a profound negative
impact on quality of life. While we now know that exaggerated muscle afferent nerve activation underlies the
exaggerated exercise pressor reflex in CKD, the mechanisms that mediate heightened muscle afferent nerve
activation to induce heightened BP reactivity remain unknown. Elucidating mechanisms of augmented exercise
pressor reflex is critical for revealing new treatment targets to improve cardiovascular risk and physical
functioning in this highly prevalent, high-risk patient population. We have compelling preliminary evidence that
muscle interstitial acidosis plays a major role in activating muscle afferent nerves, leading to an exaggerated
exercise pressor reflex in CKD. During exercise, ischemic metabolites including H+ accumulate in the muscle
interstitium and activate receptors on muscle afferent nerve endings to induce reflex increases in SNS
activation. Bicarbonate (HCO3-) is the major buffer preventing excessive reductions in muscle interstitial pH
during exercise; however, CKD patients have decreased HCO3- bioavailability starting at CKD Stage IIIB due to
an impaired ability of the diseased kidneys to excrete the daily acid load, resulting in decreased buffering
capacity. Our central hypothesis is that muscle interstitial acidosis resulting from decreased muscle buffering
capacity augments the exercise pressor reflex in CKD. We will test this hypothesis using direct
microneurographic recording of SNS activity, hemodynamics, biomarkers and innovative imaging techniques at
rest and during exercise in CKD patients. We will also determine if acute restoration of HCO3- bioavailability
ameliorates exercise-induced hypertension in CKD, and whether oral bicarbonate supplementation enhances
the beneficial effects of exercise training in CKD. Current treatment guidelines recommend bicarbonate therapy
only in CKD patients with overt acidosis ([HCO3-] ≤21 mmol/L); however, bicarbonate may be a simple, safe
and innovative method to target muscle afferent nerve activation and improve exercise hemodynamics and
function in CKD patients even without overt resting acidosis. Thus, these studies have high potential to impact
clinical practice regarding serum [HCO3-] goals, indications for bicarbonate therapy and renal rehabilitation
strategies to improve long-term cardiovascular risk in CKD.
约3700万(或15%的美国成年人)患有慢性肾病(CKD),
由于肾功能下降而导致的心血管死亡风险。CKD患者夸大了
体力活动期间血压(BP)升高,导致心血管风险增加,
身体能力差。我们先前的工作已经证明,CKD患者的这种增强的升压反应是由于
运动期间交感神经系统(SNS)的反射激活过度增加,
由肌肉传入神经激活介导,称为运动加压反射。重要的是,这样的
提高的SNS和升压反应有助于增加不良心血管事件的风险,
包括猝死,在身体活动中,以及运动不耐受,
影响生活质量。虽然我们现在知道,夸张的肌肉传入神经激活的基础,
CKD中的过度运动升压反射,介导肌肉传入神经升高的机制
激活以诱导升高的BP反应性仍然未知。增强运动的机制
升压反射对于揭示新的治疗靶点以改善心血管风险和身体健康至关重要。
在这个高流行率高风险的患者群体中发挥作用。我们有令人信服的初步证据
肌肉间质性酸中毒在激活肌肉传入神经中起主要作用,导致过度的
运动加压反射在CKD中的作用。在运动过程中,包括H+在内的缺血代谢物在肌肉中积累
并激活肌肉传入神经末梢上的受体,以诱导SNS中的反射增加
activation.碳酸氢钠(HCO 3-)是防止肌肉间质pH过度降低的主要缓冲剂
然而,CKD患者从CKD IIIB期开始HCO 3生物利用度降低,
患病肾脏排泄每日酸负荷的能力受损,导致缓冲作用下降
容量我们的中心假设是由于肌肉缓冲能力下降导致的肌肉间质性酸中毒
在CKD患者中,容量增加运动升压反射。我们将使用直接
SNS活动、血流动力学、生物标志物和创新成像技术的显微神经摄影记录
CKD患者的休息和运动期间。我们还将确定是否急性恢复HCO 3-生物利用度
改善慢性肾脏病运动诱发的高血压,以及口服碳酸氢盐补充剂是否能增强
运动训练对CKD的有益影响。目前的治疗指南推荐碳酸氢盐治疗
仅在伴有明显酸中毒([HCO 3-] ≤21 mmol/L)的CKD患者中;然而,碳酸氢盐可能是一种简单、安全的
和创新的方法来靶向肌肉传入神经激活和改善运动血液动力学,
即使没有明显的静息酸中毒,CKD患者的功能也是如此。因此,这些研究具有很高的影响潜力,
关于血清[HCO 3-]目标、碳酸氢盐治疗适应症和肾康复的临床实践
改善CKD患者长期心血管风险的策略。
项目成果
期刊论文数量(20)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Middle Cerebral Artery Pulsatility Index is Elevated in Chronic Kidney Disease.
慢性肾病患者大脑中动脉搏动指数升高。
- DOI:
- 发表时间:2022
- 期刊:
- 影响因子:0
- 作者:Jones,Touré;Sprick,Justin;DaCosta,Dana;Park,Jeanie
- 通讯作者:Park,Jeanie
α-Adrenergic receptor blockade attenuates pressor response during mental stress in young black adults.
- DOI:10.14814/phy2.14642
- 发表时间:2021-01
- 期刊:
- 影响因子:2.5
- 作者:Jeong JH;Brown ML;Kapuku G;Harshfield GA;Park J
- 通讯作者:Park J
Exercise modulates sympathetic and vascular function in chronic kidney disease.
- DOI:10.1172/jci.insight.164221
- 发表时间:2023-02-22
- 期刊:
- 影响因子:8
- 作者:Jeong, Jinhee;Sprick, Justin D.;DaCosta, Dana R.;Mammino, Kevin;Nocera, Joe R.;Park, Jeanie
- 通讯作者:Park, Jeanie
Dynamic cerebral autoregulation is intact in chronic kidney disease.
- DOI:10.14814/phy2.15495
- 发表时间:2022-11
- 期刊:
- 影响因子:2.5
- 作者:
- 通讯作者:
Vagus nerve recordings: new opportunities to investigate autonomic function in humans.
迷走神经记录:研究人类自主功能的新机会。
- DOI:10.1113/jp280300
- 发表时间:2020
- 期刊:
- 影响因子:0
- 作者:Park,Jeanie
- 通讯作者:Park,Jeanie
{{
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 }}
Jeanie Park其他文献
Jeanie Park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 }}
{{ truncateString('Jeanie Park', 18)}}的其他基金
Sympatho-inhibition with Mindfulness in Chronic Kidney Disease
慢性肾病中正念的交感抑制
- 批准号:
10706603 - 财政年份:2019
- 资助金额:
$ 69.9万 - 项目类别:
Sympatho-inhibition with Mindfulness in Chronic Kidney Disease
慢性肾病中正念的交感抑制
- 批准号:
9796614 - 财政年份:2019
- 资助金额:
$ 69.9万 - 项目类别:
Neurovascular Regulation During Exercise In Humans With Chronic Kidney Disease
慢性肾病患者运动期间的神经血管调节
- 批准号:
9220029 - 财政年份:2017
- 资助金额:
$ 69.9万 - 项目类别:
Neurovascular Regulation During Exercise in Humans With Chronic Kidney Disease
慢性肾病患者运动期间的神经血管调节
- 批准号:
10522648 - 财政年份:2017
- 资助金额:
$ 69.9万 - 项目类别:
Mechanisms of Sympathetic Overactivity in Post-traumatic Stress Disorder
创伤后应激障碍中交感神经过度活跃的机制
- 批准号:
8921491 - 财政年份:2015
- 资助金额:
$ 69.9万 - 项目类别:
Mechanisms of Sympathetic Overactivity in Post-traumatic Stress Disorder
创伤后应激障碍中交感神经过度活跃的机制
- 批准号:
9891297 - 财政年份:2015
- 资助金额:
$ 69.9万 - 项目类别:
Mechanisms of Sympathetic Overactivity in Post-traumatic Stress Disorder
创伤后应激障碍中交感神经过度活跃的机制
- 批准号:
10655338 - 财政年份:2015
- 资助金额:
$ 69.9万 - 项目类别:
Mechanisms of Sympathetic Overactivity in Post-traumatic Stress Disorder
创伤后应激障碍中交感神经过度活跃的机制
- 批准号:
10409640 - 财政年份:2015
- 资助金额:
$ 69.9万 - 项目类别:
Neurovascular Dysfunction and Oxidative Stress in Renal Failure
肾衰竭中的神经血管功能障碍和氧化应激
- 批准号:
8459604 - 财政年份:2010
- 资助金额:
$ 69.9万 - 项目类别:
The Role of Neurovascular Dysfunction and Oxidative Stress in the Exercise Intole
神经血管功能障碍和氧化应激在运动中的作用
- 批准号:
8111049 - 财政年份:2010
- 资助金额:
$ 69.9万 - 项目类别:
相似国自然基金
肿瘤微环境因子Lactic acidosis在肿瘤细胞耐受葡萄糖剥夺中的作用机制研究
- 批准号:81301707
- 批准年份:2013
- 资助金额:23.0 万元
- 项目类别:青年科学基金项目
相似海外基金
Identification of factor to induce lactic acidosis in pre-metastatic niche
转移前微环境中诱导乳酸性酸中毒的因素的鉴定
- 批准号:
23K06620 - 财政年份:2023
- 资助金额:
$ 69.9万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Carbonic Anhydrase IX Acts as a Novel CO2/HCO3- Sensor and Protects the Pulmonary Endothelial Barrier from Acidosis
碳酸酐酶 IX 作为新型 CO2/HCO3- 传感器并保护肺内皮屏障免受酸中毒的影响
- 批准号:
10678442 - 财政年份:2023
- 资助金额:
$ 69.9万 - 项目类别:
Investigation based on both basic and clinical study about acidosis caused by piganide, SGLT2 inhibitor and surgical stress
皮甘尼、SGLT2抑制剂和手术应激引起的酸中毒的基础和临床研究
- 批准号:
23K08372 - 财政年份:2023
- 资助金额:
$ 69.9万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Role of proton-sensing G-protein-coupled receptors in the regulation of microglia and microvessel endothelial cell function in brain acidosis in a mouse ischemia reperfusion model.
质子感应 G 蛋白偶联受体在小鼠缺血再灌注模型脑酸中毒中调节小胶质细胞和微血管内皮细胞功能的作用。
- 批准号:
22K07342 - 财政年份:2022
- 资助金额:
$ 69.9万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Magnetic Resonance Fingerprinting of Tumor Vascular Perfusion and Acidosis
肿瘤血管灌注和酸中毒的磁共振指纹图谱
- 批准号:
10593285 - 财政年份:2022
- 资助金额:
$ 69.9万 - 项目类别:
Acidosis in pulmonary endothelial injury and repair
酸中毒与肺内皮损伤与修复
- 批准号:
10341493 - 财政年份:2022
- 资助金额:
$ 69.9万 - 项目类别:
Acidosis in pulmonary endothelial injury and repair
酸中毒与肺内皮损伤与修复
- 批准号:
10558528 - 财政年份:2022
- 资助金额:
$ 69.9万 - 项目类别:
Characterization of an abundant lactate-utilizing Campylobacter involved in mitigating rumen acidosis
参与减轻瘤胃酸中毒的丰富乳酸利用弯曲杆菌的表征
- 批准号:
557929-2021 - 财政年份:2022
- 资助金额:
$ 69.9万 - 项目类别:
Postgraduate Scholarships - Doctoral
Impact of metabolic acidosis on muscle mitochondrial energetics, metabolic health and physical endurance in persons with chronic kidney disease
代谢性酸中毒对慢性肾病患者肌肉线粒体能量学、代谢健康和身体耐力的影响
- 批准号:
10278747 - 财政年份:2021
- 资助金额:
$ 69.9万 - 项目类别:
Impact of metabolic acidosis on muscle mitochondrial energetics, metabolic health and physical endurance in persons with chronic kidney disease
代谢性酸中毒对慢性肾病患者肌肉线粒体能量学、代谢健康和身体耐力的影响
- 批准号:
10671682 - 财政年份:2021
- 资助金额:
$ 69.9万 - 项目类别: