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: 8889253
• 负责人: ANTONIO C BIANCO
• 金额: $ 33.28万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 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 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8889253
• 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; Health; 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; coronary fibrosis; endocrine pancreas development; hormone metabolism; impaired glucose tolerance; imprint; insulin secretion; islet; mortality; mouse model; neural model; novel; 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.

性状（由申请方提供）：脱碘酶启动或终止甲状腺激素（TH）作用。在我的实验室开创性的研究揭示，激活脱碘酶（D2）和失活脱碘酶（D3）可以局部增加或减少TH信号在组织和时间特异性的方式。换句话说，D2和D3决定甲状腺信号传导的强度，而不依赖于血浆T3（生物活性TH）。我们的研究表明，这些机制可以通过各种各样的信号分子，如刺猬蛋白质家族，胆汁酸，HIF-1，NF-B和一些异生素物质来调节。这些研究表明，脱碘酶在代谢和疾病状态的控制中发挥着广泛的作用，对其的理解是本应用的重点。在这项提案中，我们专注于失活脱碘酶（D3）在三种不同组织中的作用，大脑，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易位到细胞核中以减少甲状腺激素（T3），从而减少神经元中的代谢。此外，我们已经证明，D3在心肌纤维化和心脏重塑中起着至关重要的作用，使用父系印迹D3杂合子小鼠模型。 最后，我们发表了D3基因敲除小鼠葡萄糖耐量受损，胰腺β细胞胰岛素分泌缺陷。这些发现是脑、心脏和胰腺β细胞中TH信号传导的D3控制终止的作用的基础，其对脑中的代谢调节、心脏中的肾上腺素能或血管紧张素信号传导和胰腺β细胞中的胰岛素分泌机制有影响。我们的研究表明，这些新的D3介导的适应性机制在三种不同的组织，如大脑，心脏和胰腺的设置中运行。该提案从不同组织中各种生理或病理背景的角度研究D3范式，检查D3在中风，心脏肥大和糖尿病模型中灭活甲状腺激素信号传导的影响。新发现（i）D3在神经元缺氧/缺血中起重要的保护作用，（ii）心肌D3影响心肌纤维化的肾上腺素能和血管紧张素信号传导，以及（iii）D3在胰腺β细胞发育、扩增和胰岛素分泌中至关重要，这些发现构成了该提议的基础。