Regulation of thyroid hormone levels by central and peripheral pathways

通过中枢和外周途径调节甲状腺激素水平

• 批准号: 8538955
• 负责人: Kristen Rachel Vella
• 金额: $ 14.39万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8538955
• 关键词: Academic Medical Centers; Acute; Advisory Committees; Area; Award; Biological; Biological Assay; Body Weight; Body Weight decreased; Caloric Restriction; Cell Nucleus; Cells; Clozapine; Collaborations; Commit; Designer Drugs; Development; Diabetes Mellitus; Diet; Disease; Eating; Educational process of instructing; Educational workshop; Endocrine; Endocrinology; Energy Metabolism; Environment; Experimental Designs; Extramural Activities; Faculty; Fasting; Fellowship; Funding; Future; Gene Expression; Genetic Recombination; Genetic Transcription; Glucuronosyltransferase; Goals; Grant; Health; Hepatic; Human; Hyperthyroidism; Hypothalamic structure; Hypothyroidism; In Situ Hybridization; Individual; Institution; Instruction; Israel; Knockout Mice; Laboratories; Leptin; Ligands; Liver; Manuscripts; Mediating; Medical; Medical center; Melanocortin 4 Receptor; Melanocyte stimulating hormone; Mentored Research Scientist Development Award; Mentors; Messenger RNA; Metabolic; Metabolic Diseases; Metabolism; Molecular; Mus; Neurons; Neurosecretory Systems; Nutritional; Obesity; Oxides; Pathway interactions; Peptides; Peripheral; Physiologic Thermoregulation; Physiology; Positioning Attribute; Postdoctoral Fellow; Pro-Opiomelanocortin; Process; Production; Public Speaking; Publications; Publishing; RNA; Receptor Activation; Receptor Signaling; Regulation; Repression; Research; Research Personnel; Research Proposals; Research Technics; Role; Running; Schools; Scientist; Signal Pathway; Signal Transduction; Site; Societies; Stress; Structure of nucleus infundibularis hypothalami; System; Techniques; Technology; Temperature; Testing; Thyroid Gland; Thyroid Hormones; Thyrotropin; Thyrotropin-Releasing Hormone; Time; Training; Transcriptional Regulation; Transgenic Mice; Weight; Weight maintenance regimen; Woman; Work; Writing; career; career development; cellular development; constitutive androstane receptor; deiodination; diabetic; experience; falls; feeding; hormone metabolism; in vivo; instructor; interest; medical schools; meetings; mouse model; mutant; neuropeptide Y; novel; paraventricular nucleus; pituitary thyroid axis; receptor; skills; sulfotransferase; therapeutic target

DESCRIPTION (provided by applicant): Candidate: Since graduate school, I have been interested in the homeostatic mechanisms that operate against weight loss for obese and diabetic individuals. As a postdoctoral fellow in the laboratory of Anthony Hollenberg, MD at the Beth Israel Deaconess Medical Center (BIDMC) and Harvard Medical School (HMS), my research has focused on the regulation of thyrotropin-releasing hormone (TRH) expression in the paraventricular nucleus of the hypothalamus (PVH) by both thyroid hormone and pathways important in the regulation of body weight. My work detailing the transcriptional regulation of TRH by thyroid hormone was published in Endocrinology. Recent work on the regulation of thyroid hormone levels by neuropeptide Y through the central thyroid axis and the melanocortin 4 receptor through hepatic thyroid hormone metabolism resulted in a 1st-author publication in Cell Metabolism. In addition, this work has been recognized by Women in Endocrinology and several times by The Endocrine Society. As I transition from postdoctoral fellow to Instructor, I look to target the specific neurons responsible for fasting-induced suppression of TH levels and use the results of this research to apply for extramural funding, such as an R01. My overall career goal is to become a fully independent scientist running a laboratory dedicated to answering fundamental biological questions aimed at human health and disease. The K01 award will give me the time to acquire the skills necessary to achieve this goal including training in specific techniques and the intangibles of becoming a successful independent scientist including grant and manuscript writing, lab management and teaching. Environment: The depth of expertise in the Division of Endocrinology, Metabolism and Diabetes at the BIDMC makes the Division an ideal site for training scientists in molecular physiology and metabolism. The environment at the BIDMC and HMS and its other academic medical centers within the Longwood Medical Area will provide me with outstanding opportunities for training, career development workshops and didactic courses. Importantly, my development activities during the award period include training in research techniques and in the skills necessary to become an independent investigator such as grant and manuscript writing, public speaking, collaboration, lab management and teaching. This training will be accomplished through formal coursework and individual instruction. I have identified a Primary Mentor, Dr. Anthony Hollenberg, a co-Mentor, Dr. Brad Lowell, and an Advisory Committee comprised of Drs. P. Reed Larsen and Terry Maratos-Flier who are committed to my development as an independent investigator. I will meet weekly with Dr. Hollenberg, biweekly with Dr. Lowell and formally three times a year with Drs. Larsen and Maratos- Flier to present hypotheses, experimental designs, results, and future directions. These meetings will incorporate the skill set discussed above and also integrate training in responsible conduct in research and assistance in preparing applications for tenure-track faculty positions at outstanding institutions. Research: Regulation of the hypothalamic-pituitary-thyroid (HPT) axis maintains precise circulating thyroid hormone (TH) levels. The central HPT axis includes thyrotropin-releasing hormone (TRH) release from the paraventicular nucleus (PVN) of the hypothalamus, which stimulates release of thyroid-stimulating hormone (TSH) to maintain normal TH levels. TH levels are integral to several processes including metabolism and energy expenditure. Thus, acute regulation of TH levels during periods of nutritional stress or illness is an important adaptive mechanism for survival. Metabolic signals are necessary to suppress TH levels to curb energy expenditure during a prolonged fast. Neuropeptide Y (NPY) is required for fasting-induced suppression of Trh expression in the PVN, whereas the melanocortin 4 receptor (MC4R) is required for activation of hepatic TH metabolism. Thus, fasting-induced suppression of TH levels is controlled centrally by the HPT axis and peripherally by hepatic TH metabolism. This research proposal seeks to determine the exact subsets of NPY and MC4R neurons responsible for regulation of the HPT axis and hepatic TH metabolism, respectively, and how obesity and illness disrupt this regulation under three aims: 1. To establish that NPY neurons in the arcuate nucleus signal to hypophysiotropic neurons in the PVN to regulate the HPT axis. 2. To ascertain the role of the arcuate nucleus in mediating TH-suppression of Trh expression in the PVN. 3. To discern which subsets of MC4R neurons control TH metabolism by the liver. These aims will be investigated using a combination of knockout mouse models, specialized diets to induce obesity or hypothyroidism, and Designer Receptors Exclusively Activated by Designer Drugs (DREADD) technology. DREADDs are mutant receptors that are stimulated only by the pharmacologically inert ligand clozapine-N-oxide (CNO). These mutant receptors are targeted to specific subsets of neurons using the Cre-LoxP recombination system in transgenic mice. By administering CNO to mice expressing DREADDs in NPY or MC4R neurons, this technology will pinpoint the specific subsets of NPY and MC4R neurons that control TH levels, which is the first time this technology has been used to understand neuroendocrine regulation. This project aims to provide a better understanding of how multiple metabolic signals are integrated to establish the set point of the HPT axis. Ultimately, defining the subsets of neurons that control TH levels will allow for the identification of new and specific therapeutic targets for the treatment of metabolic disorders and other diseases while also assisting in maintaining long-term weight loss.

描述（由申请人提供）：候选人：自研究生院以来，我一直对肥胖和糖尿病患者减肥的稳态机制感兴趣。作为在贝丝以色列执事医疗中心（BIDMC）和哈佛医学院（HMS）的医学博士Anthony Hollenberg实验室的博士后研究员，我的研究集中在调节甲状腺激素 - 释放激素（TRH）表达中的甲状腺纤维核（PVH）孔子（PVH）的表达（TRH）的表达（TRH）（TRH）（trh）（TRH）（TRH）（TRH）（TRH）（TRH）（TRH）（TRH）（TRH）（TRH）（PVH）（PVH）的重要性。调节体重。我的工作详细介绍了甲状腺激素对TRH的转录调节，以内分泌学发表。神经肽Y通过甲状腺中央轴和黑色素皮质蛋白4受体通过肝甲状腺激素代谢来调节甲状腺激素水平的最新工作导致细胞代谢中的第一任授权人出版物。此外，这项工作已被妇女在内分泌学中得到认可，而内分泌社会几次。当我从博士后研究员过渡到讲师时，我希望针对负责禁食诱导TH水平的特定神经元，并使用本研究的结果来应用壁外资金，例如R01。我的整体职业目标是成为一个完全独立的科学家，经营着一个致力于回答针对人类健康和疾病的基本生物学问题的实验室。 K01奖将使我有时间获得实现这一目标所需的技能，包括培训 在特定的技术以及成为成功的独立科学家的无形资产中，包括赠款和手稿写作，实验室管理和教学。环境：BIDMC内分泌，代谢和糖尿病的专业知识深度使该部门成为培训科学家分子生理学和代谢的理想场所。 BIDMC和HMS及其在Longwood医疗区域内的其他学术医疗中心的环境将为我提供培训，职业发展研讨会和教学课程的出色机会。重要的是，我在奖项期间的发展活动包括研究技术的培训以及成为授予和手稿写作，公开演讲，协作，实验室管理和教学等独立研究者所必需的技能。该培训将通过正式的课程和个人指导来完成。我已经确定了一位主要导师Anthony Hollenberg博士Brad Lowell博士和由Drs组成的咨询委员会。 P. Reed Larsen和Terry Maratos-Flier致力于我作为独立调查员的发展。我将每周一次与霍伦伯格博士见面，每两周与洛厄尔博士每两周与Drs一起正式三遍。 Larsen和Maratos-Flier提出假设，实验设计，结果和未来方向。这些会议将纳入上面讨论的技能集，并将负责任的培训集成为研究和协助的培训，以准备杰出机构的终身教师职位的申请。研究：调节下丘脑 - 垂体 - 甲状腺（HPT）轴保持精确的甲状腺激素（Th）水平。中央HPT轴包括促甲状腺蛋白释放激素（TRH）从下丘脑的旁核核（PVN）中释放，该核刺激刺激甲状腺刺激激素（TSH）的释放以维持正常水平。该水平对于包括新陈代谢和能量消耗在内的几个过程不可或缺。因此，在营养压力或疾病期间，急性调节TH水平是生存的重要适应性机制。代谢信号是抑制TH水平以遏制延长速度的能量消耗所必需的。神经肽Y（NPY）是禁食诱导的PVN中TRH表达抑制所必需的，而黑色素皮质素4受体（MC4R）是激活肝脏代谢所必需的。因此，禁食诱导的TH水平的抑制由HPT轴中心控制，并通过肝TH代谢进行外围。这项研究旨在确定负责HPT轴和肝脏代谢调节的NPY和MC4R神经元的确切子集，以及在三个目的下肥胖和疾病如何破坏这一法规：1。确定在弧形神经元中对PVN中的弓形神经元中的NPY神经元的信号，以调节PVN的量子量。 2。确定弧形核在介导PVN中TRH表达的th抑制中的作用。 3。辨别哪些MC4R神经元的子集控制肝脏的代谢。这些目标将使用敲除小鼠模型的组合，专门的饮食来诱导肥胖或甲状腺功能减退症，以及由设计师药物（Dreadd）技术专门激活的设计师受体。 Dreadds是突变受体，仅由药理学惰性配体氯氮平-N-氧化物（CNO）刺激。这些突变受体使用转基因小鼠中的CRE-LoxP重组系统针对特定的神经元子集。通过对表达NPY或MC4R神经元表达可怕的小鼠进行CNO，该技术将指出控制TH水平的NPY和MC4R神经元的特定子集，这是该技术首次用于了解神经内分泌调节。该项目旨在更好地了解如何整合多个代谢信号以建立HPT轴的设定点。最终，定义控制TH水平的神经元的子集将允许鉴定用于治疗代谢性疾病和其他疾病的新的和特定的治疗靶标，同时也有助于维持长期体重减轻。