Metabolic and Xenobiotic Control of Thyroid Hormone Metabolism

甲状腺激素代谢的代谢和外源性控制

• 批准号: 8578773
• 负责人: ANTONIO C BIANCO
• 金额: $ 18.37万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8578773
• 关键词: Adrenergic Agents; Adult; Affect; Angiotensins; Beta Cell; Bile Acids; Biological; Blood Circulation; Brain; Brain Hypoxia-Ischemia; Brain Injuries; Brain Ischemia; Cardiac; Cardiac Myocytes; Cell Differentiation process; Cell Nucleus; Cell membrane; Cell physiology; Cells; Chymosin; Data; Defect; Development; Diabetes Mellitus; Diffuse; Disease; Embryo; Erinaceidae; Event; Fibroblasts; Fibrosis; Functional disorder; Glucose Intolerance; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Hippocampus (Brain); Hormone Receptor; Hormones; Human; Hypothyroidism; Hypoxia; Immunohistochemistry; Injury; Iodide Peroxidase; Ipsilateral; Ischemia; Islets of Langerhans; Knockout Mice; Laboratories; Life; Mediating; Metabolic; Metabolism; Middle Cerebral Artery Occlusion; Modeling; Mus; Myocardial; Myocardial Infarction; Myocardium; Neuronal Hypoxia; Neurons; Nuclear Translocation; Obesity; Pancreas; Pathway interactions; Phenotype; Physiological; Plasma; Play; Pregnancy; Process; Protein Family; Publications; Publishing; Regulation; Role; Signal Transduction; Signaling Molecule; Stroke; Structure of beta Cell of islet; System; Therapeutic Intervention; Thyroid Gland; Thyroid Hormones; Thyroxine; Tissues; Triiodothyronine; Ventricular Remodeling; Xenobiotics; adrenergic; base; brain tissue; endocrine pancreas development; hormone metabolism; impaired glucose tolerance; imprint; insulin secretion; islet; mortality; mouse model; neural model; novel; public health relevance; success; type 2 deiodinase (D2)

DESCRIPTION (provided by applicant): The deiodinases initiate or terminate thyroid hormone (TH) action. Studies pioneered in my laboratory unveiled that the activating deiodinase (D2) and the inactivating deiodinase (D3) can locally increase or decrease TH signaling in a tissue- and temporal-specific fashion. In other words, D2 and D3 determine the intensity of thyroid signaling independently of plasma T3 (the biologically active TH. Our studies revealed that these mechanisms can be modulated by a wide variety of signaling molecules such as the hedgehog family of proteins, bile acids, HIF-1, NF-B, and a number of xenobiotic substances. These studies have indicated that deiodinases play a broad role in the control of metabolism and disease state, the understanding of which is the focus of this application. In this proposal, we focus on the role of inactivating deiodinase (D3) in three different tissues, brain, heart and pancreas (specifically beta cells). Our publications and preliminary data show that D3 plays a crucial role in these three tissues. For example, in brain, we have shown that D3 translocates into the nucleus to inactivate thyroid hormone (T3) to reduce metabolism in neurons. In addition, we have demonstrated that D3 plays a critical role in myocardial fibrosis and cardiac remodeling using paternally imprinted D3 heterozygous mouse models. Finally, we have published that a D3 knockout mouse has impaired glucose tolerance and has a defect in insulin secretion from pancreatic beta cells. These discoveries underlie a role of D3-controlled termination of TH signaling in brain, heart and pancreatic beta cells with repercussions for metabolic regulation in brain, adrenergic or angiotensin signaling in heart and insulin secretion mechanism in pancreatic beta cells. Our studies indicate that these novel D3 mediated adaptive mechanisms are operating in settings of three different tissues, such as brain, heart and pancreas. This proposal investigates the D3 paradigm from the perspective of various physiological or pathological contexts in different tissues, examining the effects of inactivating thyroid hormone signaling by D3 in the model of stroke, cardiac hypertrophy and diabetes. The novel findings that (i) D3 plays an important protective role in neuronal hypoxia/ischemia, (ii) myocardial D3 affects adrenergic and angiotensin signaling for myocardiac fibrosis, and that (iii) D3 is crucial n pancreatic beta cell development, expansion and insulin secretion, form the basis of this proposal.

描述(申请人提供)：脱碘酶启动或终止甲状腺激素(TH)的作用。我的实验室率先开展的研究揭示，激活的脱碘酶(D2)和失活的脱碘酶(D3)可以局部以组织和时间特异性的方式增加或减少TH信号。换句话说，D2和D3决定甲状腺信号的强度独立于血浆T3(生物活性TH。我们的研究表明，这些机制可以被广泛的信号分子调节，如刺猬蛋白家族、胆汁酸、HIF-1、NF-B和一些外来物质。这些研究表明，脱碘酶在新陈代谢和疾病状态的控制中发挥着广泛的作用，对这些方面的了解是这一应用的重点。在这项研究中，我们主要关注失活脱碘酶(D3)在三种不同的组织中的作用，脑、心脏和胰腺(特别是β细胞)。我们的出版物和初步数据表明，D3在这三种组织中起着至关重要的作用。例如，在大脑中，我们已经证明D3移位到细胞核中，以灭活甲状腺激素(T3)，从而减少神经元的新陈代谢。此外，我们还利用父系D3杂合子小鼠模型证明了D3在心肌纤维化和心脏重塑中起关键作用。最后，我们已经发表了D3基因敲除的小鼠糖耐量受损，并且胰岛β细胞分泌胰岛素的缺陷。这些发现为D3控制终止脑、心脏和胰腺β细胞中TH信号的作用奠定了基础，并对大脑的代谢调节、心脏的肾上腺素或血管紧张素信号和胰腺β细胞的胰岛素分泌机制产生影响。我们的研究表明，这些新的D3介导的适应机制在脑、心脏和胰腺等三个不同组织的环境中工作。该方案从不同组织中不同的生理或病理背景的角度来研究D3范式，以检验D3在卒中、心肌肥厚和糖尿病模型中失活甲状腺激素信号的作用。新的发现：(I)D3在神经元缺氧/缺血中起重要保护作用，(Ii)心肌D3影响肾上腺素能和血管紧张素信号转导心肌纤维化，以及(Iii)D3对胰岛β细胞的发育、扩增和胰岛素分泌起关键作用，这些都是这一提议的基础。