Vitamin D and Hormonal Mechanisms of Cardiovascular Disease in Obesity

描述（由申请人提供）：申请人的目标是加强他在肥胖心血管疾病激素机制领域的培训。肥胖是一种脂肪组织中的高肾素-血管紧张素系统（RAS）活性、低脂联素血症和维生素D缺乏的状态。这些相互交织的代谢异常导致肥胖患者心血管风险增加。申请人的既往数据支持以下假设：维生素D治疗可能是降低肥胖症患者脂肪组织RAS活性和升高循环脂联素的有效策略;这些有利的代谢特征可降低肥胖症患者的心血管风险。 申请人提出在良好控制的生理实验方案中研究60名肥胖人类受试者，该方案被设计为测试活性维生素D代谢物骨化三醇， 可调节脂肪组织RAS活性并影响肥胖患者循环脂联素水平。该项目的具体目的是测试：1）骨化三醇是否与维生素D受体相互作用，以减少肥胖症的脂肪组织肾素表达; 2）骨化三醇治疗是否会增加肥胖症的循环脂联素。虽然每个目标都解决了一个特定的相关代谢问题，但两者都使用相同的研究人群和核心研究设计，以最大限度地提高效率和资源。研究受试者将随机接受钙三醇治疗或安慰剂治疗两周。目的1将评估干预前后脂肪组织肾素的表达，以及骨化三醇的作用是否受Fok 1基因变异的影响：维生素D受体基因的功能多态性。目标2将评估干预前后的循环脂联素。 证明维生素D治疗调节调节血管疾病的激素（RAS和脂联素）的表达对于目前围绕维生素D及其潜在治疗特性的医学辩论至关重要;它将强烈支持维生素D补充剂在肥胖症中的作用。这是特别相关的，因为肥胖和维生素D缺乏症是同时发生的流行病，并且是NIH资助的大规模前瞻性随机试验的重点。在这方面，申请人的结果可以作为一个重要的生理机制来解释这些并行试验的结果;一个与NIH和NHLBI高度相关的问题。申请人在学术研究方面有着长期的成功记录，并且在研究肥胖症中的维生素D、RAS和脂联素生物学方面具有丰富的人体生理学研究经验。NIH授予他NIH F32（NRSA）和贷款偿还奖，以表彰他的相关项目。他的研究和指导环境非常适合成功完成拟议的研究，他组建了一个经验丰富的高级研究人员团队，以加强他的培训计划，并支持他未来成为独立研究员的奋进。

DESCRIPTION (provided by applicant): The applicant's objective is to enhance his training in the field of hormonal mechanisms of cardiovascular disease in obesity. Obesity is a state of high adipose-tissue renin-angiotensin system (RAS) activity, hypoadiponectinemia, and vitamin D deficiency. These intertwined metabolic abnormalities contribute to increased cardiovascular risk in obesity. The applicant's prior data support the hypothesis that vitamin D therapy may be an effective strategy to lower adipose-tissue RAS activity and raise circulating adiponectin in obesity; these favorable metabolic profiles could reduce cardiovascular risk in obesity. The applicant proposes to study 60 obese human subjects in a well-controlled physiologic experimental protocol that is designed to test whether the active vitamin D metabolite, calcitriol, can modulate adipose-tissue RAS activity and influence circulating adiponectin levels in obesity. The specific aims of this project are designed to test: 1) whether calcitriol interacts with the vitamin D receptor to reduce adipose-tissue renin expression in obesity; and 2) whether calcitriol therapy raises circulating adiponectin in obesity. Although each aim addresses a specific relevant metabolic question, both utilize the same study population and core study design to maximize efficiency and resources. Study subjects will be randomized to calcitriol therapy or placebo for two weeks. Aim 1 will evaluate adipose-tissue renin expression before and after intervention, and whether the effect of calcitriol is influenced by genetic variation at Fok1: a functional polymorphism of the vitamin D receptor gene. Aim 2 will assess circulating adiponectin before and after intervention. The demonstration that vitamin D therapy modulates the expression of hormones that mediate vascular disease (the RAS and adiponectin) is crucial to the current medical debate surrounding vitamin D and its potentially therapeutic properties; it would strongly support the role of vitamin D supplementation in obesity. This is particularly relevant since obesity and vitamin D deficiency are epidemics that occur in tandem, and are the focus of large-scale NIH funded prospective randomized trials. In this regard, the applicant's results could serve as an important physiologic mechanism to explain the results of these concurrent trials; an issue of high relevance for the NIH and NHLBI. The applicant has a long track-record of success in academic research, and extensive experience conducting human physiology studies investigating vitamin D, the RAS, and adiponectin biology in obesity. The NIH has awarded him the NIH F32 (NRSA) and Loan Repayment Awards for his related projects. His research and mentoring environment are strongly suited to successfully complete the proposed research, and he has assembled an experienced team of senior investigators to enhance his training plan and support his future endeavor of becoming an independent investigator.