Effect of surgical and pharmacological obesity treatments on hepatic fat, energy flux, and mitochondria

建议书摘要(摘要) 研究背景和影响：非酒精性脂肪性肝病(NAFLD)是肝脏疾病的主要原因 在全世界范围内，并导致早期死亡。因为青少年NAFLD主要表现为无症状，研究 应该把重点放在疾病风险特别高的青少年身上，包括那些极度肥胖的青少年 和/或多囊卵巢综合征(PCOS)。唯一被批准的治疗NAFLD的方法是生活方式干预，但 可行性和长期维护在青年时期是极具挑战性的。外科和药物性肥胖 已经探索了成人NAFLD的干预措施，新出现的数据表明垂直袖子 胃切除术(VSG)和胰升糖素样肽-1受体激动剂(GLP-1RA)可改善NAFLD。来自这两个地方的数据 成年和临床前啮齿动物模型表明，异常的肝脏线粒体和肝脏能量流是 与NAFLD的发病机制密切相关，但这些潜在的机制是否对 治疗方法仍不清楚。此外，这些手术和药物治疗还没有在 青春年华。因此，这项建议的目标是使用一种转化研究方法来评估肝脏脂肪， 手术前后代谢和线粒体功能(VSG)和药物(GLP1-RA) 干预因肥胖和/或多囊卵巢综合征导致的NAFLD高危青年(和VSG的小鼠)。我们将评估 通过肝脏MRI检查肝脏脂肪，使用口服甘油同位素示踪剂，以及通过核磁共振分析血清和肝脏同位素 量化和描述肝脏代谢动力学，并通过高分辨率测量线粒体功能 新鲜肝组织的呼吸测量和无创31Phos-MRS测定肝内磷酸盐浓度。这些 研究将为新出现的治疗方案提供极好的机制洞察力，并将改善 高危青年的近期和长期健康。 求职者和培训：我的长期职业目标是成为一名独立的、有翻译能力的学术科学家 研究计划侧重于了解潜在的分子信号事件的病理生理。 代谢性疾病，重点是非酒精性脂肪肝。我在临床前小鼠模型方面有丰富的经验，但 成为一名独立的翻译研究员，我需要在临床试验研究方面进行培训。这些建议 研究将扩展我的研究能力，包括临床试验实施，稳定同位素示踪剂，以及 31Phos夫人I还将扩展我的临床前和实验台科学研究技术，以包括小鼠存活 外科手术和脂类组学。我的机构(科罗拉多大学安舒茨医学院)提供的机会 由我的导师团队(Melanie Cree-Green博士、Darleen Sandoval博士、Jane Reusch博士、Craig Malloy博士、 布莱恩·伯格曼、劳拉·派尔)将在肝脏综合代谢方面提供出色的培训。

PROPOSAL SUMMARY (ABSTRACT) Research Background and Impact: Non-alcoholic fatty liver disease (NAFLD) is the leading cause of liver disease worldwide and leads to early mortality. Because adolescent NAFLD largely presents as asymptomatic, research should focus on adolescents at particularly high-risk for disease, which includes those with extreme obesity and/or polycystic ovary syndrome (PCOS). The only approved treatment for NAFLD is lifestyle intervention, yet feasibility and long-term maintenance is extremely challenging in youth. Surgical and pharmacological obesity interventions have been explored for treatment of NAFLD in adults, with emerging data suggesting vertical sleeve gastrectomy (VSG) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) improve NAFLD. Data from both adults and pre-clinical rodent models suggest that aberrant hepatic mitochondria and hepatic energy flux are critically involved in the pathogenesis of NAFLD, but whether these underlying mechanisms are responsive to therapy remains unknown. Further, these surgical and pharmacological treatments have not been studied in youth. Therefore, the goal of this proposal is to use a translational research approach to evaluate hepatic fat, metabolism, and mitochondrial function before and after surgical (VSG) and pharmacological (GLP1-RA) interventions in youth (and mice for VSG) at high risk for NAFLD due to obesity and/or PCOS. We will assess hepatic fat via liver MRI, use oral glycerol isotope tracers and serum and hepatic isotopomer analysis via NMR to quantify and describe dynamics of hepatic metabolism, and measure mitochondria function via high resolution respirometry of fresh liver tissue and non-invasive 31Phos-MRS for intrahepatic phosphate concentrations. These studies will provide excellent mechanistic insight into emerging therapeutic options and will improve the immediate and long-term health of at-risk youth. Candidate and Training: My long-term career goal is to be an independent, academic scientist with a translational research program focused on understanding the molecular signaling events underlying the pathophysiology of metabolic disease, with a focus on NAFLD. I have extensive experience in pre-clinical mouse models but to become an independent translational investigator, I need training in clinical trial research. These proposed studies will expand my research capabilities to include clinical trial implementation, stable isotope tracers, and 31Phos MRS. I will also expand my pre-clinical and bench science research techniques to include mouse survival surgery and lipidomics. The opportunities provided by my institution (University of Colorado Anschutz Medical Campus) and by my mentorship team (Drs. Melanie Cree-Green, Darleen Sandoval, Jane Reusch, Craig Malloy, Bryan Bergman, Laura Pyle) will provide excellent training in integrative hepatic metabolism.