Fostering patient-oriented research in cardiometabolic disease pathogenesis and prevention

促进以患者为中心的心脏代谢疾病发病机制和预防研究

• 批准号: 10657405
• 负责人: Ellen A Schur
• 金额: $ 11.86万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10657405
• 关键词: Address; Ancillary Study; Area; Astrocytes; Atherosclerosis; Attention; Autonomic Dysfunction; Award; Body Weight; Body Weight decreased; Body fat; Body mass index; Brain; Brain region; Cardiology; Cardiometabolic Disease; Cardiovascular Diseases; Carotid Arteries; Carotid Artery Plaques; Carotid Atherosclerotic Disease; Cell physiology; Central Nervous System; Data; Data Collection; Development; Diet; Dietary Assessment; Dietary Factors; Disease Outcome; Dyslipidemias; Eating; Educational Status; Electrocardiogram; Endocrinology; Enrollment; Epidemiology; Event; Faculty; Fostering; Framingham Heart Study; Fructose; Future; Generations; Gliosis; Glucose; Glucose Intolerance; Goals; Health; High Density Lipoprotein Cholesterol; Human; Hypertension; Hypothalamic structure; Image; Impairment; Incidence; Inflammation; Inflammatory; Insulin Resistance; Intake; Laboratories; Leadership; Life Style; Link; Literature; MRI Scans; Magnetic Resonance Imaging; Maternal-fetal medicine; Measures; Medicine; Mentors; Mentorship; Metabolic; Metabolic syndrome; Methodology; Microglia; Monitor; Morbidity - disease rate; Mus; Neurobiology; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Participant; Pathogenesis; Patients; Pediatrics; Photoplethysmography; Physicians; Prediabetes syndrome; Predisposition; Prevention; Productivity; Prospective, cohort study; Reporting; Research; Research Personnel; Risk Factors; Rodent; Rodent Model; Role; Scientist; Signal Transduction; Structure of nucleus infundibularis hypothalami; Testing; Training; United States; Universities; Visceral fat; Washington; Weight; Weight Gain; Work; bariatric surgery; blood glucose regulation; cardiovascular disorder risk; cardiovascular risk factor; cohort; comorbidity; diet-induced obesity; dietary; disorder risk; energy balance; experience; glucose metabolism; heart rate variability; high risk; improved; insight; mid-career faculty; mobile computing; modifiable risk; mortality; neuron loss; next generation; novel; obesity in children; obesity treatment; offspring; patient oriented; patient oriented research; programs; prospective; response; risk sharing; saturated fat; skills; successful intervention; translational study

The overarching goal of this proposal is to facilitate mentored training of junior investigators in the conduct of high-quality patient-oriented research into cardiometabolic disease pathogenesis. The PI is an Associate Professor of Medicine at the University of Washington whose research program to date has focused on the neurobiological basis of obesity and abnormal glucose metabolism. The current proposal broadens the impact of this work to include cardiovascular disease (CVD) outcomes. The candidate has a productive track record of research mentorship of Fellows and junior faculty clinician-investigators, including K awardees, and academic leadership in promoting mentorship at the departmental level. During this award, the PI will mentor a spectrum of trainees from fields including endocrinology and metabolism, cardiology, pediatrics, and maternal-fetal medicine. The PI will take didactic courses and engage in one-on-one coaching with experienced senior investigators to build mentoring skills. The PI's research program is currently focused on translational studies of cellular processes consistent with possible damage to the primary body-weight and glucose-regulating region of the hypothalamus—the arcuate nucleus. Studies in rodent models show that diet-induced weight gain is dependent on an inflammatory cellular response, known as gliosis, within the arcuate nucleus of the hypothalamus. Gliosis progresses with continued dietary exposure, eventually showing signs of neuron loss. Importantly, gliosis is detectable in mice and humans by magnetic resonance imaging (MRI). Using MRI, the PI discovered the first evidence of hypothalamic gliosis in obese humans. The investigators have gone on to show that hypothalamic gliosis 1) is independently related to insulin resistance in humans, 2) correlates with increased levels of visceral fat, 3) is present in obese children, 4) is exacerbated in type 2 diabetes mellitus (T2D), and 5) is improved by Roux-en-Y gastric bypass surgery. Our current projects seek to determine the relationship of hypothalamic gliosis to T2D and the development of glucose intolerance as well as whether hypothalamic gliosis is reversed by obesity treatment. The proposed research extends this work to investigate the implications of hypothalamic gliosis for CVD. Aim 1 tests the relation of hypothalamic gliosis to CVD in humans. To do this, the PI and trainees will conduct an ancillary study to the Framingham Heart Study (FHS). Aim 2 uses an epidemiologic approach to examine dietary risk factors for hypothalamic gliosis within FHS. Aim 3 seeks pilot and feasibility data relating atherosclerosis via carotid imaging and autonomic dysfunction to hypothalamic gliosis. A Mentoring Aim will advance the group's methodology for assessing dietary exposure. Completion of these Aims could provide novel insights into the potential role of the central nervous system in CVD development and critical scientific rationale for future K- and R- level studies. Moreover, the proposed research provides a breadth and depth of opportunities for promising trainees to gain the experience necessary to perform high-quality patient-oriented research on cardiometabolic disease.

该提案的总体目标是促进对初级调查人员进行指导培训 以患者为中心的高质量心脏代谢疾病发病机制研究。 PI 是一名助理 华盛顿大学医学教授，迄今为止的研究项目主要集中在 肥胖和糖代谢异常的神经生物学基础。当前提案扩大了影响 这项工作包括心血管疾病 (CVD) 的结果。该候选人拥有以下卓有成效的记录： 研究员和初级教员临床医生研究员（包括 K 获奖者）和学术人员的研究指导 领导部门推动指导工作。在此颁奖期间，PI 将指导一系列 来自内分泌与代谢、心脏病学、儿科、母胎等领域的学员 药品。 PI 将参加教学课程并与经验丰富的资深人士进行一对一辅导 调查员建立指导技能。 PI 的研究项目目前专注于转化研究 细胞过程与对主要体重和葡萄糖调节可能造成的损害一致 下丘脑区域——弓状核。啮齿动物模型研究表明饮食引起的体重增加 依赖于弓状核内的炎症细胞反应，称为神经胶质增生 下丘脑。神经胶质增生随着持续的饮食暴露而进展，最终显示出神经元损失的迹象。 重要的是，通过磁共振成像（MRI）可以检测到小鼠和人类的神经胶质增生。使用 MRI，PI 发现了肥胖人群下丘脑神经胶质增生的第一个证据。调查人员已继续 表明下丘脑神经胶质增生 1) 与人类胰岛素抵抗独立相关，2) 与 内脏脂肪水平增加，3) 存在于肥胖儿童中，4) 在 2 型糖尿病中加剧 (T2D) 和 5) 通过 Roux-en-Y 胃绕道手术得到改善。我们当前的项目旨在确定 下丘脑神经胶质增生与 T2D 和葡萄糖耐受不良发展的关系以及是否 肥胖治疗可以逆转下丘脑神经胶质增生。拟议的研究将这项工作扩展到调查 下丘脑神经胶质增生对 CVD 的影响。目标 1 测试下丘脑神经胶质增生与 CVD 的关系 人类。为此，PI 和学员将进行弗雷明汉心脏研究 (FHS) 的辅助研究。 目标 2 使用流行病学方法来检查 FHS 内下丘脑神经胶质增生的饮食危险因素。目的 3 寻求通过颈动脉成像和自主神经功能障碍与动脉粥样硬化相关的试点和可行性数据 下丘脑神经胶质增生。指导目标将推进该小组评估饮食暴露的方法。 完成这些目标可以为中枢神经系统的潜在作用提供新的见解。 CVD 发展以及未来 K 和 R 水平研究的关键科学原理。此外，拟议的 研究为有前途的受训者提供了广度和深度的获得经验的机会 对心脏代谢疾病进行高质量的、以患者为导向的研究是必要的。