Fostering patient-oriented research in cardiometabolic disease pathogenesis and prevention

这项提议的总体目标是促进初级调查人员在行为方面的指导培训 高质量的面向患者的心脏代谢性疾病发病机制研究。私家侦探是助理 华盛顿大学的医学教授，他的研究项目到目前为止一直集中在 肥胖和糖代谢异常的神经生物学基础。目前的提案扩大了影响 这项工作的结果包括心血管疾病(CVD)。候选人在以下方面有卓有成效的记录： 研究员和初级教师临床医生-研究人员(包括K奖获得者)和学术人员的研究指导 在部门层面推动导师制方面发挥领导作用。在这个奖项中，PI将指导一个频谱 来自内分泌和新陈代谢、心脏病、儿科和母婴等领域的受训人员 医药。PI将参加授课课程，并与经验丰富的资深学生进行一对一的指导 调查人员建立指导技能。国际翻译协会的研究项目目前侧重于翻译研究。 与对初级体重和葡萄糖调节可能的损害相一致的细胞过程 下丘脑的区域--弓状核。对啮齿动物模型的研究表明，饮食导致体重增加 依赖于弓状核内的炎性细胞反应，称为胶质细胞增生症 下丘脑。神经胶质增生症随着饮食的持续暴露而发展，最终显示出神经元丢失的迹象。 重要的是，通过磁共振成像(MRI)可以在小鼠和人类身上检测到胶质细胞增多症。使用MRI，PI 发现了肥胖人类下丘脑胶质细胞增多症的第一个证据。调查人员已经继续进行 表明人类下丘脑胶质细胞增多症1)与胰岛素抵抗独立相关，2)与 内脏脂肪水平增加，3)肥胖儿童，4)2型糖尿病加重 (T2D)和5)Roux-en-Y胃旁路手术改善。我们目前的项目试图确定 下丘脑胶质细胞增多症与T2D和糖耐量异常的关系 肥胖治疗可逆转下丘脑胶质细胞增多症。建议的研究将这项工作扩展到调查 下丘脑胶质细胞增生症对脑血管病的意义。目的1检测大鼠下丘脑胶质细胞增多症与脑血管病的关系。 人类。为此，PI和受训人员将对弗雷明翰心脏研究(FHS)进行一项辅助研究。 目的2采用流行病学方法研究FHS患者下丘脑胶质细胞增多症的饮食危险因素。目标 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 下丘脑胶质细胞增多症。指导目标将推动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在脑内的潜在作用提供新的见解。 心血管疾病的发展和未来K-和R-水平研究的关键科学理论基础。此外，建议的 研究为有前途的受训者提供了获得经验的广度和深度机会 有必要开展高质量的以患者为中心的心脏代谢性疾病研究。

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.