Vitamin D and Hormonal Mechanisms of Cardiovascular Disease in Obesity

肥胖症中维生素 D 和心血管疾病的激素机制

• 批准号: 8466366
• 负责人: Anand Vaidya
• 金额: $ 16.11万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-07 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8466366
• 关键词: Address; Adipocytes; Adipose tissue; Alleles; Award; Biology; Biopsy; Calcitriol; Cardiovascular Diseases; Cardiovascular system; Data; Distant; Endocrine Glands; Environment; Epidemic; Etiology; Exhibits; Funding; Future; Genetic Polymorphism; Genetic Variation; Genotype; High Prevalence; Hormonal; Hormones; Human; Hypertension; Individual; Insulin Resistance; Intervention; Measures; Mediating; Medical; Mentors; Metabolic; Methods; Mission; Morbidity - disease rate; National Heart, Lung, and Blood Institute; National Research Service Awards; Obesity; Participant; Peptides; Physiological; Physiology; Placebos; Population Study; Property; Prospective Studies; Protocols documentation; Randomized; Receptor Gene; Recruitment Activity; Renin; Renin-Angiotensin System; Research; Research Design; Research Personnel; Resources; Role; Study Subject; Supplementation; System; Testing; Therapeutic; Tissues; Training; United States National Institutes of Health; Vascular Diseases; Vitamin D; Vitamin D Deficiency; Vitamin D2; Vitamin D3 Receptor; adiponectin; cardiovascular risk factor; cost effective; design; experience; human subject; improved; inhibitor/antagonist; paracrine; prospective; public health relevance; randomized trial; research study; subcutaneous; success

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.

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肾素-血管紧张素系统（RAS）活性高、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会增加肥胖患者患心血管疾病的风险。申请人先前的数据支持维生素D治疗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的假设；这些有利的代谢特征可以降低肥胖患者的心血管风险。申请人拟在一个控制良好的生理实验方案中对60名肥胖受试者进行研究，旨在测试活性维生素D代谢物骨化三醇