Development of obesity and metabolic clinical research programs

肥胖和代谢临床研究项目的开发

• 批准号: 10697802
• 负责人: Kong Chen
• 金额: $ 91.21万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10697802
• 关键词: 3-Dimensional; Adrenergic Agonists; Adult; African American; Agonist; Agreement; Anti-Obesity Agents; Area; Basal metabolic rate; Biochemistry; Blood; Body Composition; Body Surface; Body Surface Area; Body Temperature; Body measure procedure; Brown Fat; COVID-19 pandemic; Child; Chronic; Clinical; Clinical Protocols; Clinical Research; Clothing; Collaborations; Control Groups; Data; Data Analyses; Diabetes Mellitus; Dietary intake; Disease; Dose; Energy Intake; Energy Metabolism; Equation; Ethnic Origin; FDA approved; Face; Fasting; Fatty acid glycerol esters; Female; Food; Gender; Goals; Heart Rate; Height; Hour; Human; Inpatients; Institutional Review Boards; Interruption; Intervention; Journals; Lasers; Manuscripts; Measurement; Measures; Metabolic; Methods; Molecular Biology; Movement; Mythology; Natural History; Obesity; PET/CT scan; Paper; Participant; Pharmaceutical Preparations; Pharmacology; Phase; Physical activity; Physiological; Positron-Emission Tomography; Process; Property; Protocols documentation; Publications; Publishing; Race; Randomized; Regulation; Research; Research Personnel; Rest; Role; Shivering; Skeletal Muscle; Skin; Specificity; Sympathetic Nervous System; Techniques; Temperature; Therapeutic; Thermogenesis; Thinness; Training; United States National Institutes of Health; Weight; Woman; X-Ray Computed Tomography; antagonist; beta-adrenergic receptor; biological adaptation to stress; clinical center; clinical investigation; cohort; coronavirus disease; design; energy balance; environmental change; experience; fight against; healthy volunteer; human subject; improved; interest; male; men; military operation; novel strategies; obesity development; obesity management; predictive modeling; primary outcome; programs; receptor; recruit; response; sex; study population; total energy expenditure; urinary; volunteer

During the majority of FY22, we still face the significant challenges related to the COVID-19 pandemic and the intermittent shutdowns, staff and supply shortages of the clinical research programs associated with healthy volunteers; however, we made progresses in the following areas. 1. Our ongoing clinical protocol titled Energy expenditure responses to a range of environmental temperatures around the thermal neutral zone (12-DK-0097, NCT01568671) was designed to improve our understanding of dynamic regulation of energy expenditure in response to subtle changes in environmental temperature. In particular, we are interested in studying the capacity of (facultative) cold-induced thermogenesis in humans, defined as an increase in energy expenditure (EE or heat production) to a changed environmental temperature. Combined with the ongoing research on brown adipose tissue (BAT) and its role in cold-induced thermogenesis (CIT) in our and other labs, such clinical research is generating substantial interests in the field of energy metabolism and obesity. We measure energy expenditure continuously in a 5-hour period (0800-1300 fasted) in the room calorimeter with randomized environmental temperature ranging between 16 - 31C (61-88F) in 10-13 consecutive days (inpatient). We also carefully measure skeletal muscle shivering, body movements, heart rate, skin and core body temperatures, and stress responses by blood and urinary markers, while controlling for physical activity, clothing, and dietary intake. To date, we successfully studied fifteen (15) healthy lean male volunteers as our normative control group, nine (9) healthy obese male volunteers matched for age and race/ethnicity, sixteen (16) lean female volunteers (11 had repeated measurements in follicular and luteal menstrual phases), twelve (13) older lean male volunteers (11 with complete data), and thirteen (13) young lean African-American male (12 with complete data) volunteers. The BAT data from lean and obese men were published in PNAS in 2017; CIT data from lean and obese men was published in JCEM in 2019. We further compared our data to other cold exposure studies in a publication related to military operations published in 2020. The BAT data from 12 lean women was published in Obesity 2020, and the EE and other physiological data is currently being analyzed for a paper submission. We are also amending this protocol to expand the recruitment to include more gender and race equity in our study population. 2. With the interests for brown adipose tissue (BAT) continue to grow, we are using the BAT PET/CT images in the 12-DK-0097 to train our postbac IRTAs during the COVID shutdown period. We also continue to train other BAT clinical researchers to analyze PET/CT images using the process that we developed. In FY22, the NIH Clinical Center acquired their first research PET/MR scanner. We have established a close collaboration with the CC PET Dept and are amending the protocol to develop a new approach to quantify BAT and validate it against our current PET/CT technique. 3. For the protocol 13-DK-0200, NCT01950520, we completed Cohort 1 studies (n=16) of using a pharmacologic approach to regulating sympathetic nervous system (SNS) by different beta-adrenergic receptors varying receptor specificity and agonist/antagonist properties and measure their effects on resting EE in thermoneutral vs. cold-stimulated states. We are currently analyzing the data and preparing manuscripts. We continue to recruit study participants for Cohort 2 (studying the single-dose effects of 4 different FDA approved anti-obesity drugs. Before the COVID-19 pandemic that paused our studies, we accrued 9 study participants so far (8 completed, one study was interrupted). An interim analysis showed that we would reach our primary outcome (5% increase of BMR in one drug) with 16 subjects. In addition, our collaboration with Dr. Aaron Cypess in the Cohort 3 study (n=13) on the dose-response of a 3-adrenergic agonists (mirabegron) to stimulate human BAT and energy expenditure resulted in a publication in Diabetes in 2018, which then emerged into a chronic mirabegron study (4-weeks) in women. This study has also resulted in a publication in the Journal of Clinical Investigation in 2020. Using these experiences, we published a review titled opportunities and challenges in the therapeutic activation of human energy expenditure and thermogenesis to manage obesity in Journal of Biological Chemistry (2020). And another mythological review on mirabegron and human BAT was published in Methods in Molecular Biology in FY22. 4. We acquired a 3D laser-guided body surface scanner to our lab during FY21. The goal of using this non-invasive scanner is to accurately measure body surface area (BSA) in human subjects rather than relying on simple prediction models using weight, height, and sex parameters which were developed over 60-70 years ago. We are planning a new natural history protocol (IRB approved 000617 NCT05398783 and waiting for regulatory clearance before we start recruiting subjects) to examine the agreement between measured BSA and BSA estimated by previously established prediction equations in both healthy children and adults, those with recent changes in weight, and those with various forms of disease. If successful, we plan to add this as another non-invasive measurement to our body composition lab. We also plan to compare laser measured BSA with body composition and energy expenditure parameters to investigate the underlying mechanism(s) that BSA may contribute to human energy expenditure and balance.

在22财年的大多数期间，我们仍然面临与19日大流行有关的重大挑战，以及与健康志愿者有关的临床研究计划的间歇性关闭，员工和供应短缺；但是，我们在以下领域取得了进步。 1。我们正在进行的临床协议，标题为对热中性区域周围一系列环境温度（12-DK-0097，NCT01568671）的一系列环境温度的反应，旨在提高我们对环境温度微妙变化的动态能量支出的理解。特别是，我们有兴趣研究（兼性）冷诱导的人类生热的能力，该能力定义为能量消耗（EE或热量产生）到变化的环境温度变化的能力。结合对棕色脂肪组织（BAT）的持续研究及其在我们和其他实验室中冷诱导的生热发生（CIT）中的作用，这种临床研究在能量代谢和肥胖领域产生了巨大的兴趣。我们在室内量热计的5小时（0800-1300禁食）中连续测量能量支出，随机环境温度在连续10-13天（住院）内随机环境温度在16-31C（61-88F）之间。我们还仔细测量骨骼肌发抖，身体运动，心率，皮肤和核心体温以及血液和尿液标记物的压力反应，同时控制体育锻炼，衣服和饮食摄入量。迄今为止，我们成功地研究了15（15）个健康的精益男性志愿者，作为我们的规范对照组，九（9）健康的肥胖男性志愿者匹配年龄和种族/种族/种族/种族/种族/种族，16岁（16）个精益女性志愿者（11名瘦的女性志愿者（11个重复测量了卵泡和脂肪阶段和脂肪阶段的二型男性二线（13）年轻人（13）老年人（13）老年人（13）（13）（13）（13）（13）（13）（13）（13）（13）（13）（13）（11）非洲裔美国男性（12个具有完整数据）志愿者。瘦肉和肥胖男人的蝙蝠数据于2017年在PNAS上发布；来自精益和肥胖男性的CIT数据于2019年在JCEM发表。我们在与2020年发表的军事行动有关的出版物中进一步将我们的数据与其他冷暴露研究进行了比较。肥胖2020年发表了12名精益妇女的BAT数据，目前正在分析EE和其他生理数据，以提交论文提交。我们还正在修改该协议，以扩大招聘，以在我们的研究人群中包括更多的性别和种族公平。 2。随着棕色脂肪组织（BAT）的兴趣不断增长，我们正在使用12-DK-0097中的BAT PET/CT图像在Covid关机期间训练我们的邮政BAC IRTAS。我们还继续培训其他BAT临床研究人员，使用我们开发的过程分析PET/CT图像。在22财年，NIH临床中心收购了他们的第一个研究宠物/MR Scanner。我们已经与CC PET部门建立了密切合作，并正在修改协议，以开发一种新方法来量化BAT并根据我们当前的PET/CT技术进行验证。 3。对于协议13-DK-0200，NCT01950520，我们通过不同的β-肾上腺素能受体改变受体特异性和激动剂/拮抗剂的特性，并测量其在热对方中的效果来调节同步受体的特异性，并通过不同的β-肾上腺素受体来调节交感神经系统（SNS），以调节交感神经系统（SNS）的效果。我们目前正在分析数据并准备手稿。 We continue to recruit study participants for Cohort 2 (studying the single-dose effects of 4 different FDA approved anti-obesity drugs. Before the COVID-19 pandemic that paused our studies, we accrued 9 study participants so far (8 completed, one study was interrupted). An interim analysis showed that we would reach our primary outcome (5% increase of BMR in one drug) with 16 subjects. In addition, our collaboration with Dr. Aaron在队列3的研究中，CYPESS（n = 13）对3-肾上腺素能激动剂（Mirabegron）的剂量反应刺激人类的蝙蝠和能量消耗，导致2018年糖尿病的出版物，然后在该研究中涉及妇女的2020年临床研究。一项评论，题为《人类能量消耗和热生成的治疗激活的机会和挑战》，以管理生物化学杂志（2020）中的肥胖症。关于米拉贝隆和人类蝙蝠的另一篇神话回顾在《分子生物学方法》中发表了22财年。 4。我们在财政部期间向我们的实验室获得了3D激光引导的身体表面扫描仪。使用这种非侵入性扫描仪的目的是准确测量人类受试者的身体表面积（BSA），而不是使用60-70年前开发的重量，身高和性别参数依靠简单的预测模型。我们正在计划一项新的自然历史协议（IRB批准的000617 NCT05398783，并在我们开始招募受试者之前等待监管清除），以检查由健康的儿童和成人的先前确定的预测方程所估算的测量BSA和BSA之间的一致性，这些方程的重量是近期体重的变化，以及各种疾病的变化。如果成功，我们计划将其添加为另一种非侵入性测量，并将其添加到我们的身体组成实验室中。我们还计划将激光测量的BSA与身体成分和能量消耗参数进行比较，以研究BSA可能有助于人类能量消耗和平衡的基本机制。