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

摘要 高血压是导致死亡的主要原因，起源于儿童时期。儿童时期的高血压很常见， 会导致心脏和肾脏损伤，并预示着成人高血压，但50%的患者治疗反应差 并增加心脏和肾脏损伤的风险。预测治疗反应可能会改善健康 在人的一生中，但目前还不存在预测因素。治疗反应差的原因和方法 儿童的心脏和肾脏损伤尚未完全了解；这些差距限制了患者的护理。初步 数据表明，血管紧张素-(1-7)、尿酸和血钾的变化可能在早期血管紧张素转换酶的发展中起关键作用。 高血压和器官损伤。然而，这还没有在儿童高血压中进行研究。这样做的目的是 K23将启动一个有指导的研究项目和培训计划，以a)建立临床证据基础 血管紧张素-(1-7)在儿童高血压中的作用，以及b)获得所需的培训、教育、经验和数据 过渡到独立的、以患者为中心的研究生涯，专注于解决基本的 高血压防治心血管机制的科学与临床研究 一生中都有疾病。这项针对5至17岁高血压儿童的前瞻性队列研究将 检测血液和尿液中的血管紧张素-(1-7)、尿酸和血钾，并使用新的因果推断方法 分析它们与血压的关系以及心脏和肾脏损伤的测量方法。具体目标是： I)确定高血压患者与正常血压对照组的血管紧张素-(1-7)是否不同，并调节其作用 血压降低对受试者心脏和肾脏损伤的影响；ii)评估血管紧张素-(1-7)是否可以预测 受试者的治疗反应；以及iii)确定血管紧张素-(1-7)是否调节尿酸之间的关系 受试者的酸和心脏损伤以及红晕和肾脏损伤。中心假设是：1)血管紧张素- (1-7)在受试者中低于对照组，并在降低血压对改善结果的影响中起中介作用 在受试者中；2)血管紧张素-(1-7)预测受试者的治疗反应；3)血管紧张素-(1-7)介导 尿酸与心脏损伤、血钾与肾损伤的关系。结果将导致 通过确定疾病进展方式的差异，提高对儿童高血压的理解 对治疗的反应，并提供高血压相关器官损伤如何发生的关键证据。这将是 通过定义新的疾病类型和告知新的治疗策略来改善患者护理。候选人 是一名终身制助理教授，拥有75%的受保护时间和研究资金、设备和人员 得到部门和机构的支持。应聘者有一个明确的指导学习计划， 提供大型队列研究、高级统计学、化验和细胞机制以及临床方面的培训 心血管测量。这项K23奖项将提供必要的资源，以支持候选人的 在公共卫生日益重要的领域过渡到独立的研究生涯。

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.