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。儿童期高血压很常见， 导致心脏和肾脏损伤，并预测成人高血压，但治疗反应不良发生在50%的 儿童和增加心脏和肾脏损伤的风险。预测治疗反应可以改善健康 在一个人的一生中，但目前还没有预测。治疗反应差的原因以及如何 儿童心脏和肾脏损伤的发展还没有完全了解，这些差距限制了病人的护理。初步 数据表明血管紧张素-（1-7）、尿酸和klotho的变化可能对早期发展至关重要。 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。这个目标 K23将启动一个指导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，和B）获得所需的培训、教育、经验和数据， 过渡到一个独立的以病人为导向的研究事业，重点是解决基础之间的差距 科学和临床研究高血压的机制，以预防和治疗心血管疾病 疾病在整个生命周期。这项针对5至17岁高血压儿童的前瞻性队列研究将 测量血液和尿液中的血管紧张素-（1-7）、尿酸和klotho，并使用新的因果推断方法， 分析它们与血压以及心脏和肾脏损伤的关系。具体目标是： i）确定血管紧张素-（1-7）在高血压受试者与血压正常对照者中是否存在差异并介导效应 ii）评估血管紧张素-（1-7）是否预测受试者的心脏和肾脏损伤; iii）确定血管紧张素-（1-7）是否介导了受试者的尿酸水平与治疗反应之间的关系。 酸和心脏损伤以及klotho和肾损伤。主要假设是：1）血管紧张素- (1-7)与对照组相比，受试者的血压较低，并介导了血压降低对改善结局的影响 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 尿酸与受试者心脏损伤和klotho与受试者肾损伤的相关性。结果将导致 通过确定疾病进展的差异，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 通过定义新的疾病类型和提供新的治疗策略来改善患者护理。候选 是一个终身助理教授，有75%的时间和研究资金，设备和人员受到保护 得到了部门和机构的支持。候选人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，分析和细胞机制以及临床 心血管检查此K23奖项将提供必要的资源，以支持候选人的 过渡到一个日益重要的公共卫生领域的独立研究生涯。

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.