Vitamin D and Hormonal Mechanisms of Cardiovascular Disease in Obesity

描述(申请人提供)：申请人的目标是加强他在肥胖的心血管疾病的荷尔蒙机制领域的培训。肥胖是一种脂肪组织肾素-血管紧张素系统(RAS)活性高、脂联素低和维生素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。申请人先前的数据支持这样一种假设，即维生素D疗法可能是降低肥胖患者脂肪组织RAS活性和提高循环脂联素的有效策略；这些有利的代谢特征可以降低肥胖患者的心血管风险。申请人建议以受控良好的生理学实验方案研究60名肥胖的人类受试者，该实验方案旨在测试活性维生素D代谢物骨化三醇， 可调节脂肪组织RAS活性，影响肥胖患者循环中的脂联素水平。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，以减少肥胖症患者脂肪组织肾素的表达；以及2)骨化三醇治疗是否增加肥胖症患者的循环脂联素。虽然每个目标都解决一个特定的相关代谢问题，但两者都使用相同的研究群体和核心研究设计，以最大限度地提高效率和资源。研究对象将被随机接受骨化三醇治疗或安慰剂治疗，为期两周。目的1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维生素D受体基因功能多态Fok1基因遗传变异的影响。目的2评估干预前后循环脂联素的变化。维生素D治疗可调节调节血管疾病的激素(RAS和脂联素)的表达，这一证明对当前围绕维生素D及其潜在治疗特性的医学辩论至关重要；这将有力地支持维生素D补充在肥胖中的作用。这一点特别重要，因为肥胖和维生素D缺乏是同时发生的流行病，也是NIH资助的大规模前瞻性随机试验的重点。在这一点上，申请人的结果可以作为一个重要的生理机制来解释这些同时进行的试验的结果；这是一个与NIH和NHLBI高度相关的问题。申请者在学术研究方面有长期的成功记录，并拥有丰富的人类生理学研究经验，研究肥胖中的维生素D、RAS和脂联素生物学。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，他已经组建了一支经验丰富的高级调查团队，以加强他的培训计划，并支持他未来成为一名独立调查人员的努力。

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.