Fostering patient-oriented research in cardiometabolic disease pathogenesis and prevention

本提案的总体目标是促进对初级调查员进行指导培训， 高质量的以患者为导向的心脏代谢疾病发病机制研究。PI是助理 他是华盛顿大学的医学教授，迄今为止，他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。目前的建议扩大了影响 包括心血管疾病（CVD）的结果。候选人有一个富有成效的记录， 研究员和初级教师临床研究员的研究指导，包括K获奖者，以及学术 在部门层面推广师友关系方面发挥领导作用。在此期间，PI将指导一系列 来自内分泌学和代谢学、心脏病学、儿科学和母胎学等领域的受训人员 药PI将参加教学课程，并与经验丰富的高级管理人员进行一对一的指导。 调查员培养辅导技能。PI的研究计划目前主要集中在转化研究 细胞过程与可能损害的主要体重和葡萄糖调节一致 下丘脑的区域-弓状核。在啮齿动物模型中的研究表明，饮食诱导的体重增加 是依赖于一种炎症细胞反应，称为胶质细胞增生，在弓状核的 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）可以在小鼠和人类中检测到神经胶质增生。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。调查人员已经开始 显示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型糖尿病中加重 (T2D)5）Roux-en-Y胃旁路手术可改善胃排空障碍。我们目前的项目旨在确定 下丘脑神经胶质增生与T2 D和葡萄糖耐受不良的关系以及是否 下丘脑神经胶质增生通过肥胖治疗逆转。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的影响目的1：探讨下丘脑胶质细胞增生与脑血管病的关系。 人类为此，PI和受训者将进行一项辅助研究，以进行心脏起搏研究（FHS）。 目的2采用流行病学方法研究FHS患者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。 这些目标的完成可以为中枢神经系统的潜在作用提供新的见解， CVD发展和未来K-和R-水平研究的关键科学原理。此外，拟议的 研究为有前途的学员提供了广泛和深入的机会，以获得经验 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。

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.