Metabolic and Xenobiotic Control of Thyroid Hormone Metabolism

描述（由申请人提供）：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了激活脱碘酶（D2）和灭活脱碘酶（D3）可以局部地以组织特异性和时间特异性的方式增加或减少TH信号。换句话说，D2和D3独立于血浆T3（生物活性TH）决定甲状腺信号的强度。我们的研究表明，这些机制可以被多种信号分子调节，如刺猬蛋白家族、胆汁酸、HIF-1、NF-B和一些外源物质。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。在这一建议中，我们关注失活脱碘酶（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易位到核中使甲状腺激素（T3）失活，以减少神经元的代谢。此外，我们已经证明D3在心肌纤维化和心脏重塑中发挥关键作用，使用父亲印迹D3杂合小鼠模型。最后，我们发表了D3敲除小鼠的糖耐量受损，并且胰腺β细胞分泌胰岛素有缺陷。这些发现奠定了3d控制的脑、心脏和胰腺β细胞中TH信号终止的作用，对脑代谢调节、心脏肾上腺素能或血管紧张素信号和胰腺β细胞胰岛素分泌机制产生影响。我们的研究表明，这些新的D3介导的适应机制在三种不同的组织中运作，如大脑、心脏和胰腺。本研究拟从不同组织的各种生理或病理背景出发，探讨D3在脑卒中、心肌肥大和糖尿病模型中灭活甲状腺激素信号的作用。新的发现(i) D3在神经元缺氧/缺血中起重要的保护作用，（ii）心肌D3影响心肌纤维化的肾上腺素和血管紧张素信号传导，以及（iii） D3在胰腺β细胞的发育、扩张和胰岛素分泌中至关重要，构成了这一建议的基础。

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.