Mechanisms of CNS Vitamin D Receptor in Weight Regulation

项目摘要 肥胖在三分之一的美国成年人和儿童中很普遍，并使美国的医疗保健系统付出代价。 每年数十亿美元。维生素D水平低与肥胖有很强的关联，但潜在的 因果关系尚未确定。已经进行了多项临床试验，将维生素D用作 肥胖症的治疗方法，结果相互矛盾。肥胖对患者的广泛影响及其社会成本 因此迫切需要建立有效的治疗方法。然而，治疗肥胖和减少 在我们了解其发病和进展的机制之前， 肥胖肥胖和维生素D水平低的可能机制之一是通过大脑。 越来越多的证据表明，大脑在关键的体重调节区域有维生素D受体 维生素D会阻碍血脑屏障的运输。然而，潜在的CNS 还没有研究过维生素D受体对体重的调节。西斯利博士的长期研究目标 是解开儿童肥胖症的维生素D依赖机制， 为儿科人群提供新的治疗选择。在本提案中，Sisley博士将重点关注 维生素D可能在大脑中起作用以调节体重的机制。她的初步数据显示 维生素D受体的活性配体1，25-二羟基维生素D3（骨化三醇; 1，25 D3） 显著降低肥胖啮齿类动物的食物摄入量、体重，特别是脂肪量 直接注入大脑此外，她还证明了1，25 D3对POMC神经元的去极化有直接作用， 这是众所周知的减少食物摄入量。最后，她的数据显示，维生素D受体的生理作用， 大脑以下具体目标将使用先进的体内和分子技术来确定 维生素D介导的减肥机制。在目标1中，她将确定POMC中的VDR是否 神经元是使用Cre-lox方法进行正常体重调节所必需的。在目标2中，她将测试 假设1，25 D3通过POMC神经元中的VDR发出信号以通过体内食物引起厌食 摄入实验，ChIP评估VDR与POMC启动子的结合，以及基因组/转录组学 实验目的3将研究黑素皮质素-4受体的需求，黑素皮质素-4受体是黑素皮质素的下游靶点。 POMC，在1，25 D3的厌食作用中。这个指导职业发展奖的主要目标是 推动博士Sisley向前在她追求一个独立的研究生涯。西斯利博士有一个强大的 她的研究生奖学金的出版和赠款记录，并在体内生理学方面具有出色的技术 啮齿动物的代谢测试。她的职业发展计划包括非正式和正式的核培训 受体生物学和基因组水平的研究技术。此外，她还将接受老鼠训练， 遗传学、神经解剖学/生理学和维生素D信号传导。她将结合专题讨论会， 国家会议、教学课程和个性化指导，以实现她的培训目标。她 目前在贝勒医学院的任命给了她一个强大的研究环境， 核受体的专家，基因组技术的核心设施，以及重要的机构支持（如 她的启动资金和机构支持信证明）。她在Dr. 核受体专家大卫摩尔，以及新的指导下博士南希韦格尔（维生素D） 和通过UT西南，乔尔Elmquist博士（下丘脑体重调节）。此外，她 捐助者，以帮助她在她的训练的各个方面的进步。这种组合的圆周率很强， 导师，并在一个著名的研究机构集中培训目标，使Sisley博士最终 作为一名独立的调查员。

PROJECT SUMMARY Obesity is prevalent in one third of American adults and children and costs the American health care system billions of dollars yearly. There are strong associations of low vitamin D levels with obesity, yet an underlying causal relationship has not been identified. Multiple clinical trials have been performed to use vitamin D as a treatment for obesity with conflicting results. The extensive impact of obesity on patients and its cost to society make the establishment of effective treatments urgently necessary. However, treating obesity and decreasing its prevalence cannot occur until we understand the mechanisms underlying the onset and progression of obesity. One of the possible mechanisms linking obesity and low vitamin D levels is through the brain. Accumulating evidence indicates that the brain has receptors for vitamin D in key weight regulatory regions and that vitamin D has impaired transport across the blood-brain-barrier. However, the potential CNS regulation of weight by the vitamin D receptor has not been studied. Dr. Sisley's long-term research objective is to unravel the vitamin D-dependent mechanisms underpinning childhood obesity and to translate these findings into new therapeutic options for the pediatric population. In this proposal, Dr. Sisley will focus on the mechanisms by which vitamin D may act in the brain to regulate weight. Her preliminary data have revealed the ability of the active ligand for the vitamin D receptor, 1,25-dihydroxyvitamin D3 (calcitriol; 1,25D3) to dramatically reduce food intake, body weight, and specifically fat mass in obese rodents when delivered directly into the brain. Additionally, she demonstrates 1,25D3 has direct actions to depolarize POMC neurons, which are known to decrease food intake. Last, her data show a physiological role for the vitamin D receptor in the brain. The following specific aims will use advanced in vivo and molecular techniques to determine the mechanisms underlying vitamin-D mediated weight loss. In Aim 1, she will determine if the VDR in POMC neurons is required for normal weight regulation using a Cre-lox approach. In Aim 2, she will test the hypothesis that 1,25D3 signals through the VDR in POMC neurons to cause anorexia through in vivo food intake experiments, ChIP assessment of VDR binding to the POMC promoter, and genomic/transcriptomic experiments. Aim 3 will investigate the requirement of melanocortin-4 receptors, a downstream target of POMC, in the anorectic effect of 1,25D3. The primary goal of this mentored career development award is to advance Dr. Sisley forward in her pursuit of an independent research career. Dr. Sisley has a strong publication and grant record from her fellowship and has excellent techniques in the physiological in vivo metabolic testing of rodents. Her career development plan includes informal and formal training in nuclear receptor biology and genomic level investigational techniques. Additionally, she will gain training in mouse genetics, neuroanatomy/physiology, and vitamin D signaling. She will use a combination of focused-symposia, national meetings, didactic courses, and individualized mentorship to achieve her training objectives. Her current appointment at the Baylor College of Medicine gives her a strong research environment with both experts in nuclear receptors, core facilities in genomic techniques, and significant institutional support (as evidenced by her start-up funds and Letter of Institutional Support). She has strong mentorship under Dr. David Moore, an expert in nuclear receptors, as well as new mentorship under Dr. Nancy Weigel (vitamin D) and through UT Southwestern, Dr. Joel Elmquist (hypothalamic weight regulation). Additionally, she has contributors to aid her progress in every aspect of her training. This combination of a strong PI, excellent mentorship, and focused training goals at a renowned research institution poises Dr. Sisley for ultimate success as an independent investigator.