Non-classical cardiometabolic determinants of parathyroid hormone

 描述（由申请人提供）：拟议的项目旨在研究甲状旁腺激素的非经典心脏代谢决定因素，有两个具体目标：1）测试急性和持续使用 ACE 抑制对健康受试者和原发性甲状旁腺功能亢进受试者的甲状旁腺激素（PTH）水平的影响，2）研究 PTH 与肥胖的关系是否具有长期特异性（即由内脏肥胖驱动）。这一目标源于越来越多的证据支持PTH（一种重要的钙调节激素）与肾素-血管紧张素-醛固酮系统（RAAS）之间的相互作用，而肾素-血管紧张素-醛固酮系统是血压和容量状态的关键调节剂。在目标 1 中，我将利用这种相互作用的知识来测试 ACE 抑制对 RAAS 的抑制是否会导致正常和原发性甲状旁腺功能亢进受试者的 PTH 降低。为此，将招募20名正常受试者和20名原发性甲状旁腺功能亢进受试者进行介入研究，分别检测常用ACE抑制剂卡托普利和赖诺普利治疗前1小时和1周后的钙调节标志物，包括PTH和钙，以及RAAS激素水平。对于目标 2，将使用动脉粥样硬化多种族研究 (MESA) 的数据进行横断面分析，MESA 是一项针对中年男性和女性的多种族 NIH 前瞻性队列研究。使用人口统计数据、生化标志物和腹部 CT 数据，分析 PTH 水平与各种腹部脂肪库的关联，调整 PTH 的众多混杂因素，以测试独立关联。为了成功实现这些目标，我的研究培训计划包括由我的导师团队（Gail Adler 博士、Anand Vaidya 博士和 Ian De Boer 博士）进行的培训，以及通过哈佛临床和转化科学催化剂计划进行的临床研究正式培训。此外，我在布莱根妇女医院和哈佛催化剂中心的研究环境非常适合成功完成这些目标。

 DESCRIPTION (provided by applicant): The project proposed aims to investigate non-classical, cardiometabolic determinants of parathyroid hormone, with two specific aims: 1) to test the effect of acute and sustained use of ACE inhibition on parathyroid hormones (PTH) levels in healthy subjects and subjects with primary hyperparathyroidism, and 2) to investigate whether the association of PTH with adiposity is depot specific (i.e. driven by visceral adiposity) The context of these two aims arises from growing evidence supporting an interaction between PTH, a critical calcium-regulatory hormone, and the renin-angiotensin-aldosterone system (RAAS), which is a key regulator of blood pressure and volume status. In Aim 1, I will utilize knowledge of this interaction to test whether suppression of the RAAS by ACE inhibition causes a decrease in PTH in normal and primary hyperparathyroidism subjects. For this purpose, 20 normal subjects and 20 subjects with primary hyperparathyroidism will be recruited to perform an interventional study, testing calcium-regulatory markers, including PTH and calcium, and RAAS hormones levels before and after 1 hour and 1 week of treatment with commonly used ACE inhibitors, captopril and lisinopril, respectively. For Aim 2, a cross-sectional analysis will e performed using data from the Multi-Ethnic Study of Atherosclerosis (MESA), an ethnically diverse NIH- prospective cohort study of middle-aged men and women. Using demographic data, biochemical markers, and abdominal CT data, the association of PTH level with various abdominal adipose depots will be analyzed, adjusting for numerous confounders of PTH, to test for an independent association. In order to successfully achieve these goals, my research training plan includes training by my mentoring team (Dr. Gail Adler, Dr. Anand Vaidya, and Dr. Ian De Boer), and formal training in clinical investigation through the Harvard Catalyst Program for Clinical and Translational Science. In addition, my research environment at Brigham and Women's Hospital and the Harvard Catalyst is well-suited to allow successful completion of these aims.