Regulation of energy balance after gastric bypass in mice

小鼠胃绕道手术后能量平衡的调节

• 批准号: 8249009
• 负责人: Vincent Aguirre
• 金额: $ 14.27万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8249009
• 关键词: Achievement; Address; Adverse effects; Afferent Neurons; Anatomic structures; Animals; Appointment; Area; Attenuated; Autonomic nervous system; Bariatrics; Basic Science; Behavioral; Biometry; Body Weight; Body Weight decreased; Brain; Brain Stem; Brown Fat; Characteristics; Clinical; Clinical Research; Clinical Trials; Comorbidity; Complement; Core Facility; Data; Development; Diabetes Mellitus; Diphtheria Toxin; Disease; Eating; Economic Burden; Energy Metabolism; Engineering; Ensure; Environment; Exposure to; Faculty; Feeding behaviors; Fellowship; Funding; Gastric Bypass; Genetic; Goals; Grant; Health; Human; Hyperglycemia; Hyperinsulinism; Intake; International; Journals; Knockout Mice; Laboratories; Laboratory Research; Liver; Mediating; Medical; Medicine; Melanocortin 4 Receptor; Mentors; Metabolic; Metabolic Diseases; Metabolism; Molecular; Motor; Motor Neurons; Mus; Nerve; Nervous system structure; Neuraxis; Neurons; Nutrient; Obese Mice; Obesity; Obesity associated disease; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Peer Review; Pharmaceutical Preparations; Phenotype; Physiological; Population; Postdoctoral Fellow; Procedures; Process; Public Health; Publications; Reagent; Regulation; Research; Research Design; Resolution; Risk; Rodent; Role; Scientist; Sensory; Signal Transduction; Specificity; Structure; Sympathetic Nervous System; Techniques; Testing; Therapeutic; Tissues; Training; Vagus nerve structure; Weight; Work; Writing; bariatric surgery; blood glucose regulation; career; career development; clinical efficacy; diabetic; effective therapy; energy balance; experience; gastrointestinal; glucose metabolism; health economics; improved; interest; lectures; meetings; member; mouse model; nerve supply; professor; receptor expression; receptor function; research study; response; responsible research conduct; symposium

DESCRIPTION (provided by applicant): The combination of my prior research and clinical training uniquely situate me to investigate how Roux- en-Y gastric bypass (RYGB) causes weight loss and improves diabetes. Specifically, the surgical expertise that I obtained during my post-doctoral fellowship involving bariatric surgery in rodents complements the intensive basic science training in molecular mechanisms of diabetes that I received during my doctoral training. This surgical and intellectual expertise poises me to perform disease-oriented research investigating the physiologic and molecular effects of bariatric surgery on obesity and related metabolic disease, as proposed in this application. My immediate career goals include the further development of my research laboratory in terms of data, reagents, publications, and additional funding. My recent faculty appointment and substantial commitment of the Departmental of Medicine to my research efforts have greatly facilitated this process. My long-term career goals include continued publication of my data in peer-reviewed scientific journals, to further establish myself as an independent scientist, and to become recognized as a leader in the fields of obesity, diabetes, and gastrointestinal regulation of metabolism. Realizing these achievements will ensure my continued career advancement, particularly the transition from assistant to associate professor, and beyond. The research environment at UT Southwestern, particularly as coordinated within the Taskforce for Obesity Research at UT Southwestern (TORS), provides me with the ideal opportunity to attain these goals. Specifically, my daily exposure to the TORS faculty, and the UT Southwestern faculty at large, will provide the experience and mentoring I need to ensure my continued development as a clinical scientist. My career development will involve both informal interactions with my mentor, TORS faculty, and members of their laboratories as well as more structured opportunities that include weekly meetings with my mentor, regular participation and presentation at divisional and departmental WIP ("works-in-progress") meetings, departmental seminars, and international/national scientific symposia. I will also have the opportunity to lecture trainees regarding my clinical and research expertise, and attend classes involving biostatistics, research design, scientific grant writing, research management, and the Responsible Conduct of Research. In addition, I will have access to the full complement of technical capabilities represented in the TORS laboratories as well as the TORS Mouse Metabolic Phenotyping Core Facility, the extensive use of which is detailed in this proposal. Thus, UT Southwestern is the ideal environment to help me in achieving my goals. My prior training ensures that I will maximize these opportunities, and any others that may arise. I have focused my research efforts on the problem of obesity because of the magnitude of its public health threat. While even modest weight loss improves patient outcomes, most current behavioral and medical therapies are ineffective. In contrast, bariatric surgery induces substantial weight loss and improvement of related comorbidities. Unfortunately, due to its inherent risk, it is only available to the severely obese. Safer options that may be more broadly applied are needed. We have developed a technique to perform RYGB, the most commonly performed bariatric procedure in the US, on obese mice to understand how it so effectively induces weight loss and improves diabetes. This weight loss occurs largely due to an increase in metabolic rate. Additionally, we have determined that RYGB fails to induce weight loss or improve diabetes in genetically-manipulated mice that lack the melanocortin-4 receptor (MC4R), an important regulator of body weight. This finding enables us to directly investigate the role of MC4R and putative target tissues in the beneficial effects of RYGB. It will further facilitate the development of safer, less-invasive therapies that may mimic the clinical efficacy of bariatric surgery. The MC4R is expressed in structures of the autonomic nervous system (ANS) that are involved in the regulation of body weight and glucose metabolism (which is dysregulated in diabetes), including the vagus nerve and motor neurons of the sympathetic nervous system (SNS). The vagus nerve relays information regarding nutrient intake to the brain and is involved in the responsive modulation of feeding behavior and glucose metabolism. Recent genetic experiments in mice have demonstrated that MC4R in the vagus nerve and motor neurons of the SNS are involved in the regulation of glucose metabolism and metabolic rate, respectively. These observations suggest that RYGB may mediate its effects on body weight, metabolic rate, and diabetes through MC4R in these autonomic components. In this application, we propose experiments to directly investigate this hypothesis. To address our aims, we will perform RYGB on mice that have been genetically-engineered to express MC4R exclusively in these components of the ANS. Complete phenotypic characterization of post-surgical animals will identify target tissues and MC4R-dependent physiologic mechanisms through which RYGB induces weight loss, increases metabolic rate, and improves diabetes. Medications that modulate MC4R function are already in clinical trials. These findings are critical in that they will identify target tissues to which pharmacologic therapy that modulates MC4R function may be directed, thereby facilitating the development of pharmacologic agents with increased specificity of action and clinical efficacy while limiting the risk of side effects.

描述（由申请人提供）：我之前的研究和临床培训相结合，使我能够独特地研究 Rouxen-Y 胃绕道手术 (RYGB) 如何导致体重减轻和改善糖尿病。具体来说，我在博士后研究期间获得的涉及啮齿动物减肥手术的外科专业知识补充了我在博士培训期间接受的糖尿病分子机制的强化基础科学培训。这种外科和智力方面的专业知识使我能够进行以疾病为导向的研究，调查减肥手术对肥胖和相关代谢疾病的生理和分子影响，如本申请中所提出的。我的近期职业目标包括在数据、试剂、出版物和额外资金方面进一步发展我的研究实验室。我最近的教职任命和医学系对我的研究工作的大力支持极大地促进了这一过程。我的长期职业目标包括继续在同行评审的科学期刊上发表我的数据，进一步确立自己作为一名独立科学家的地位，并成为肥胖、糖尿病和胃肠代谢调节领域公认的领导者。实现这些成就将确保我持续的职业发展，特别是从助理到副教授等的过渡。德克萨斯大学西南医学中心的研究环境，特别是在德克萨斯大学西南医学中心肥胖研究工作组 (TORS) 的协调下，为我提供了实现这些目标的理想机会。具体来说，我每天接触 TORS 教师以及整个 UT 西南大学的教师，将为我提供所需的经验和指导，以确保我作为一名临床科学家的持续发展。我的职业发展将涉及与我的导师、TORS 教员及其实验室成员的非正式互动，以及更有条理的机会，包括与我的导师每周举行会议、定期参与部门和部门 WIP（“正在进行的工作”）并进行演示。 ") 会议、部门研讨会和国际/国家科学研讨会。我还将有机会向学员讲授我的临床和研究专业知识，并参加涉及生物统计学、研究设计、科学资助写作、研究管理和负责任的研究行为的课程。此外，我还将获得 TORS 实验室以及 TORS 小鼠代谢表型核心设施所代表的全套技术能力，本提案详细介绍了其广泛使用。因此，德州大学西南分校是帮助我实现目标的理想环境。我之前的培训确保我能够最大限度地利用这些机会以及可能出现的任何其他机会。由于肥胖对公共健康威胁的严重性，我将研究重点放在肥胖问题上。尽管即使是适度的体重减轻也能改善患者的治疗效果，但目前大多数的行为和药物疗法都是无效的。相比之下，减肥手术可显着减轻体重并改善相关合并症。不幸的是，由于其固有的风险，它仅适用于严重肥胖者。需要更广泛应用的更安全的选择。我们开发了一种技术，可以对肥胖小鼠进行 RYGB（美国最常进行的减肥手术），以了解它如何有效地减轻体重并改善糖尿病。这种体重减轻很大程度上是由于新陈代谢率的增加。此外，我们还确定，对于缺乏黑皮质素 4 受体 (MC4R)（体重的重要调节剂）的基因改造小鼠，RYGB 无法诱导体重减轻或改善糖尿病。这一发现使我们能够直接研究 MC4R 和假定靶组织在 RYGB 有益作用中的作用。它将进一步促进更安全、侵入性较小的疗法的开发，这些疗法可以模仿减肥手术的临床疗效。 MC4R 在参与体重调节和葡萄糖代谢（糖尿病中失调）的自主神经系统 (ANS) 结构中表达，包括迷走神经和交感神经系统 (SNS) 的运动神经元。迷走神经将有关营养摄入的信息传递给大脑，并参与进食行为和葡萄糖代谢的响应调节。最近的小鼠基因实验表明，迷走神经和 SNS 运动神经元中的 MC4R 分别参与葡萄糖代谢和代谢率的调节。这些观察结果表明，RYGB 可能通过这些自主神经组件中的 MC4R 介导其对体重、代谢率和糖尿病的影响。在此应用中，我们提出实验来直接研究这一假设。为了实现我们的目标，我们将对经过基因工程改造、仅在 ANS 的这些组件中表达 MC4R 的小鼠进行 RYGB。手术后动物的完整表型特征将确定靶组织和 MC4R 依赖性生理机制，RYGB 通过这些机制诱导体重减轻、提高代谢率和改善糖尿病。调节 MC4R 功能的药物已进入临床试验。这些发现至关重要，因为它们将确定调节 MC4R 功能的药物治疗可能针对的靶组织，从而促进药物制剂的开发，提高作用特异性和临床疗效，同时限制副作用的风险。