The role of angiotensin-(1-7) in hypertension and hypertension-induced heart and kidney damage

血管紧张素-(1-7)在高血压及高血压心肾损害中的作用

基本信息

批准号：
10228071
负责人：
Andrew Michael South
金额：
$ 15.66万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-03 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10228071
关键词：
Address Adult Albuminuria Aldosterone Angiotensin-Converting Enzyme Inhibitors Animal Model Area Basic Science Biochemical Biological Assay Biological Markers Blood Blood Pressure Cardiovascular Diseases Cardiovascular system Cause of Death Cells Child Childhood Clinic Clinical Clinical Research Clinical Trials Cohort Studies Collaborations Coupled Data Development Development Plans Disease Disease Progression Equipment Etiology Excretory function Foundations Funding Future Goals Grant Health Heart Heart Injuries Human Resources Hypertension Impairment Injury Injury to Kidney Institution K-Series Research Career Programs Kidney Kidney Failure Knowledge Learning Left Ventricular Hypertrophy Life Lisinopril Longevity Longitudinal cohort study Measures Mediating Mediation Mediator of activation protein Mentored Patient-Oriented Research Career Development Award Mentors Methods Organ Outcome Oxidative Stress Patient Care Patients Pediatric cohort Pharmaceutical Preparations Phenotype Plasma Positioning Attribute Prediction of Response to Therapy Prevalence Prospective cohort study Public Health Race Renin Renin-Angiotensin System Research Research Project Grants Research Training Resources Risk Role Time Training Training and Education Uric Acid Urine aged angiotensin I (1-7)anti aging assay development blood pressure reduction cardiovascular effects cardiovascular health career career development decubitus ulcer experience experimental study follow-up heart damage improved improved outcome klotho protein normotensive novel novel therapeutics organ injury patient oriented patient oriented research prevent professor recruit renal damage research and development response sex skill acquisition statistics targeted treatment tenure track treatment response treatment strategy

项目摘要

ABSTRACT Hypertension is a leading cause of death and originates in childhood. Hypertension in childhood is common, causes heart and kidney injury, and predicts adult hypertension, but poor treatment response occurs in 50% of children and increases the risk of heart and kidney injury. Predicting treatment response may improve health throughout one’s life, but no predictors currently exist. The reasons for poor treatment response and how children develop heart and kidney injury are not fully understood; these gaps limit patient care. Preliminary data suggest changes to angiotensin-(1-7), uric acid, and klotho may be critical to the early development of hypertension and organ injury. However, this has not been studied in pediatric hypertension. The goal of this K23 is to initiate a mentored research project and training plan to a) establish a foundation of clinical evidence of angiotensin-(1-7) in pediatric hypertension and b) obtain training, education, experience, and data needed to transition to an independent patient-oriented research career focused on addressing gaps between basic science and clinical research in the mechanisms of hypertension in order to prevent and treat cardiovascular disease across the lifespan. This prospective cohort study of children aged 5 to 17 years with hypertension will measure angiotensin-(1-7), uric acid, and klotho in blood and urine and use novel causal inference methods to analyze their relationships to blood pressure and measures of heart and kidney injury. The specific aims are: i) determine if angiotensin-(1-7) differs in hypertension subjects vs. normotensive controls and mediates effect of blood pressure lowering on heart and kidney injury in subjects; ii) evaluate if angiotensin-(1-7) predicts treatment response in subjects; and iii) determine if angiotensin-(1-7) mediates the relationships between uric acid and heart injury and klotho and kidney injury in subjects. The central hypotheses are that 1) angiotensin- (1-7) is lower in subjects vs. controls and mediates the effect of reduced blood pressure on improved outcomes in subjects; 2) angiotensin-(1-7) predicts treatment response in subjects; and 3) angiotensin-(1-7) mediates the associations of uric acid with heart injury and klotho with kidney injury in subjects. Results will lead to an improved understanding of pediatric hypertension by identifying differences in how the disease progresses in response to treatment and providing crucial evidence of how hypertension-related organ injury occurs. This will improve patient care by defining new types of disease and informing new treatment strategies. The Candidate is a tenure-track assistant professor with 75% protected time and research funds, equipment, and personnel supported by the department and institution. The Candidate has a well-defined mentored learning plan that provides training in large cohort studies, advanced statistics, assay and cellular mechanisms, and clinical cardiovascular measures. This K23 award will provide the resources necessary to support the Candidate’s transition to an independent research career in an area of growing public health importance.

抽象的高血压是死亡的主要原因，起源于童年。童年时期的高血压很普遍，导致心脏和肾脏损伤，并预测成人高血压，但治疗反应不佳，其中50％儿童并增加了心脏和肾脏损伤的风险。预测治疗反应可以改善健康通过一个人的生活，但目前没有预测因素。治疗反应不佳的原因以及如何儿童发育心脏和肾脏损伤尚不完全了解。这些差距限制了患者护理。初步的数据表明，血管紧张素（1-7），尿酸和klotho的变化对于早期发展至关重要高血压和器官损伤。但是，这尚未研究小儿高血压。目标的目标 K23是为了启动指导的研究项目和培训计划，以建立临床证据的基础血管紧张素 - （1-7）在儿科高血压和b）获得所需的培训，教育，经验和数据过渡到独立的面向患者的研究职业，重点是解决基本之间的差距高血压机制的科学和临床研究，以预防和治疗心血管整个生命周期的疾病。这项对高血压5至17岁儿童的前瞻性队列研究将在血液和尿液中测量血管紧张素（1-7），尿酸和克洛索，并使用新的因果推理方法分析他们与血压以及心脏和肾脏损伤的关系。具体目的是： i）确定血管紧张素 - （1-7）高血压受试者与正常的控制和培养物的效果是否差异受试者心脏和肾脏损伤的血压降低； ii）评估血管紧张素 - （1-7）是否预测受试者的治疗反应； iii）确定血管紧张素 - （1-7）是否介导尿液之间的关系酸和心脏损伤以及受试者的Klotho和肾脏损伤。中心假设是1）血管紧张素 - （1-7）在受试者与对照中较低，并介导降低血压对改善预后的影响在受试者中； 2）血管紧张素 - （1-7）受试者的预测治疗反应； 3）血管紧张素 - （1-7）培养尿酸与心脏损伤的关联和受试者的肾损伤的关联。结果将导致通过确定疾病进展的差异，对小儿高血压的了解得以提高对治疗的反应，并提供有关高血压相关器官损伤的关键证据。这会通过定义新型疾病并告知新的治疗策略，改善患者护理。候选人是一名终身助理助理教授，拥有75％的受保护时间和研究基金，设备和人员得到部门和机构的支持。候选人有一个明确定义的剖宫产计划提供大型队列研究，高级统计，测定和细胞机制以及临床的培训心血管措施。该K23奖将提供支持候选人的必要资源过渡到独立研究职业，该职业在公共卫生的重要性越来越重要。