Regulation of neuronal function by mitochondrial uncoupling

通过线粒体解偶联调节神经元功能

• 批准号: 10664198
• 负责人: Kristin Claflin
• 金额: $ 15.53万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10664198
• 关键词: ATP Synthesis Pathway; Address; Adipose tissue; Adult; Amphibia; Animals; Appetite Depressants; Attenuated; Biology; Body Weight; Body Weight decreased; Brain; Brain region; Brown Fat; Cardiovascular Diseases; Cell Respiration; Cells; Central Nervous System; Chemicals; Chronic; Consumption; Data; Data Set; Development; Development Plans; Eating; Educational workshop; Electron Microscopy; Energy Intake; Energy Metabolism; Epidemic; Food Energy; Future; Gene Expression; Generations; Genetic; Glucose; High Fat Diet; Homeostasis; Homologous Gene; Hydrogen Peroxide; Hypertension; Hypothalamic structure; Ingestion; Inner mitochondrial membrane; Iowa; Knock-out; Knockout Mice; Knowledge; Liver diseases; Mammals; Measures; Mentorship; Metabolic; Metabolic Diseases; Metabolism; Mitochondria; Molecular; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Neurons; Neuropeptides; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Organelles; Overweight; Oxidative Stress; Oxygen Consumption; Pathogenesis; Physiological; Population; Positioning Attribute; Prevention; Production; Protons; Publications; Reactive Oxygen Species; Regulation; Research; Research Personnel; Respiration; Role; SF1; Secure; Signal Pathway; Structure of nucleus infundibularis hypothalami; Synaptosomes; Testing; Therapeutic; Thermogenesis; Training; Transcript; Universities; Viral; Viral Vector; Weight Gain; career; career development; combat; diet-induced obesity; energy balance; excessive weight gain; experimental study; improved; in silico; insight; knock-down; mind control; mitochondrial dysfunction; mitochondrial uncoupling protein; mouse model; new therapeutic target; nonalcoholic steatohepatitis; novel; novel therapeutics; obesity management; obesity prevention; obesity treatment; overexpression; oxidative damage; pharmacologic; single-cell RNA sequencing; symposium; targeted agent; uncoupling protein 1; viral rescue

PROJECT SUMMARY / ABSTRACT Obesity is a major contributor to the epidemic of metabolic diseases including type II diabetes, hypertension, cardiovascular disease, and liver disease. Excess weight gain is the result of a chronic imbalance between caloric intake and energy expenditure, and while several pharmacological agents target energy intake to promote body weight loss, no current options are successful in the long-term management of obesity. Thus, a greater understanding of the central mechanisms that contribute to obesity are required for both its prevention and treatment. Numerous studies have implicated mitochondrial dysfunction in neurons because of excess consumption of nutrients in the pathogenesis of obesity. Previous publications have demonstrated that the inner mitochondrial membrane protein uncoupling protein 1 (UCP1), renowned for its role in heat production in thermogenic adipose tissue, is also expressed in the central nervous system (CNS), however, the function of neuronal UCP1 is completely unknown. Our preliminary data unexpectedly demonstrates that UCP1 is expressed in the ventromedial hypothalamus (VMH) of adult mice and that its expression is metabolically regulated. Consequently, there is a need to understand how UCP1 functions and whether it’s activation within the CNS can also regulate energy homeostasis as it does in brown adipose tissue. The next steps addressing these needs are to pursue the overall objective of this application: (i) determine the extent to which UCP1 in the VMH influences energy balance, and (ii) investigate if neuronal UCP1 activity attenuates the production of reactive oxygen species (ROS) to regulate energy homeostasis. We will investigate our central hypothesis that activation of UCP1 within the VMH chronically reduces ROS to promote negative energy balance. We will test our hypothesis using novel genetic mouse models and viral vector constructs that knockout or overexpress UCP1 specifically in the VMH to determine whether modulation of neuronal UCP1 activity regulates body weight following cold exposure or consumption of high fat diet. Moreover, we will be able to investigate whether UCP1 in the VMH can chronically reduce ROS to regulate energy homeostasis, as well as determine how modulating its expression regulates mitochondrial dynamics. The experiments proposed in this application are expected to identify novel signaling pathways that provide new insights into the treatment and prevention of obesity. Rationale for this project is that discovering the function of central UCP1 may contribute to future discovery efforts to identify and test new therapeutic targets to treat obesity. In addition, an outlined career development plan to elevate my knowledge of mitochondrial biology by leveraging mentorships, technical training, seminars, conferences, and R01 workshops is described in the application. The University of Iowa has committed its support and facilities to allow Dr. Claflin to complete the proposed research and participate in their extensive training seminars. Completion of the proposed 5-year research and training plans will prepare Dr. Claflin for an independent research career and assist in securing an R01 from the NIDDK.

项目摘要/摘要 肥胖是代谢性疾病流行的主要原因，包括II型糖尿病、高血压， 心血管疾病和肝脏疾病。过度的体重增加是长期不平衡的结果， 热量摄入和能量消耗，而一些药理学试剂靶向能量摄入，以促进 体重减轻，目前没有选择是成功的长期管理肥胖。更大的， 了解导致肥胖的中枢机制对于预防肥胖和 治疗许多研究表明，由于过量的线粒体功能障碍， 营养素的消耗在肥胖症的发病机制。以前的出版物已经证明， 线粒体膜蛋白解偶联蛋白1（UCP 1），以其在产热中的作用而闻名， 产热脂肪组织也在中枢神经系统（CNS）中表达，然而， 神经元UCP 1完全未知。我们的初步数据出乎意料地表明，UCP 1是 在成年小鼠的下丘脑腹内侧（VMH）中表达，并且其表达是代谢性的 监管.因此，有必要了解UCP 1是如何发挥作用的，以及它是否在细胞内被激活。 中枢神经系统也可以调节能量稳态，就像它在棕色脂肪组织中所做的那样。下一步解决 这些需求是为了追求本申请的总体目标：（i）确定UCP 1在多大程度上 VMH影响能量平衡，以及（ii）研究神经元UCP 1活性是否减弱了 活性氧（ROS）调节能量稳态。我们将研究我们的中心假设， VMH内UCP 1的激活长期减少ROS以促进负能量平衡。我们将测试 我们的假设使用了新的遗传小鼠模型和敲除或过表达UCP 1的病毒载体构建体， 特别是在VMH中，以确定神经元UCP 1活性的调节是否调节体重 寒冷暴露或食用高脂肪饮食后。此外，我们将能够调查UCP 1是否 在VMH可以慢性减少ROS调节能量稳态，以及确定如何调节 其表达调节线粒体动力学。在本申请中提出的实验预计将 确定新的信号通路，为治疗和预防肥胖提供新的见解。 该项目的基本原理是，发现中央UCP 1的功能可能有助于未来的发现 努力确定和测试新的治疗目标，以治疗肥胖。此外，职业发展概述 我计划通过导师制、技术培训、研讨会， 会议和R 01研讨会在应用程序中描述。爱荷华州大学承诺， 支持和设施，使克拉夫林博士能够完成拟议的研究，并参与他们的广泛的 培训研讨会。完成拟议的5年研究和培训计划将为克拉夫林博士 独立的研究生涯，并协助从NIDDK获得R 01。