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Physiologic Role of Type 2 Deiodinase in Skeletal Muscle

2 型脱碘酶在骨骼肌中的生理作用

基本信息

批准号：
7179346
负责人：
BRIAN W KIM
金额：
$ 13.39万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-02-20 至 2010-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7179346
关键词：
2,4-thiazolidinedione 3-monoiodothyronine Adrenergic Agents Animals Area Biological Brain Brown Fat Ca(2+)-Transporting ATPase Cell Culture Techniques Cells Collaborations Condition Data Development Dose Endocrinology Enzymes Fatty Acids Genes Goals Homeostasis Hormones Human Iodide Peroxidase Literature MM form creatine kinase Mediating Metabolic Metabolic Pathway Metabolic stress Metabolism Metformin Modeling Molecular Mus Muscle Cells Muscle Fibers Nuclear Partner in relationship Physiological Physiology Pioglitazone Pituitary Gland Positioning Attribute Proteolysis Range Regulation Research Personnel Role Serum Signal Transduction Skeletal Muscle Skeletal system Source Specificity System Techniques Testing Tetanus Helper Peptide Thiazolidinediones Thyroid Gland Thyroid Hormones Thyroxine Time Tissues Transgenic Mice Transgenic Organisms Triiodothyronine Triiodothyronine Receptors Ubiquitination Work adrenergic blood glucose regulation energy balance experience extracellular hormone regulation in vivo insulin sensitivity oxidation prohormone promoter receptor type 2 deiodinase (D2)

项目摘要

DESCRIPTION (provided by applicant): The goal of the work described in this proposal is to characterize the physiologic role of the type 2 deiodinase (D2) in human skeletal muscle. D2 converts the prohormone thyroxine (T4) to 3,5,3'-triiodothyronine (T3), the active hormone. Our hypothesis is that, in human skeletal muscle, D2 regulates T3- responsive metabolic pathways by modulating the saturation of nuclear T3-receptors (TRs). This hypothesis is founded on data from brain, pituitary, and brown adipose tissue showing that D2-catalyzed T4 to T3 conversion is an important source of intranuclear T3, and on the literature establishing T3 as an important regulator of metabolic processes in skeletal muscle. Our approach to test this hypothesis primarily utilizes commercially available primary human skeletal myocytes in culture (HSMM cells), but also includes a new transgenic "SkD2" mouse with conditional, skeletal muscle-specific expression of D2. In Specific Aim I, we will characterize the regulation of D2 in human skeletal myocytes, and then test the hypothesis that D2- catalyzed T4 to T3 conversion can increase nuclear T3 concentration in these cells enough to alter the expression of T3-responsive genes. In Specific Aim II, we will evaluate the potential for T4, via D2, to modulate intermediary metabolism in these cells. In Specific Aim III, we will create a transgenic mouse with conditional expression of D2 in its skeletal muscle via the tet-off system. We will use this mouse to study the physiologic role of skeletal muscle D2 under normal conditions and during periods of metabolic stress. In addition, we will determine the effect of D2 induction on in vivo glucose homeostasis in collaboration with Dr. Jason Kim of the Yale Mouse Metabolic Phenotypic Center. These studies will provide the candidate with experience in a wide range of molecular biological techniques. He will become an expert in thyroid hormone action, while also gaining valuable exposure in the areas of energetics and metabolism, positioning him well to continue his development towards becoming an independent investigator in endocrinology.

描述(由申请人提供)：这项建议中描述的工作的目标是表征人类骨骼肌中2型脱碘酶(D2)的生理作用。D2将前激素甲状腺素(T4)转化为活性激素3，5，3‘-三碘甲腺原氨酸(T3)。我们的假设是，在人类骨骼肌中，D2通过调节核T3受体(TRs)的饱和来调节T3反应的代谢途径。这一假说建立在来自脑、垂体和棕色脂肪组织的数据基础上，表明D2催化的T4到T3的转换是核内T3的重要来源，并基于文献证实T3是骨骼肌代谢过程的重要调节因子。我们验证这一假设的方法主要是利用商业上可获得的原代培养的人类骨骼肌细胞(HsMM细胞)，但也包括一种新的转基因“SkD2”小鼠，该小鼠具有条件的、骨骼肌特异性的D2表达。在特定的目标I中，我们将表征D2在人类骨骼肌细胞中的调节，然后检验D2催化的T4到T3转换可以增加这些细胞中的核T3浓度，从而改变T3反应基因的表达的假设。在特定的目标II中，我们将评估T4通过D2调节这些细胞的中间代谢的潜力。在特定的目标III中，我们将通过tet-off系统创建一个在骨骼肌中有条件表达D2的转基因小鼠。我们将利用这只小鼠来研究骨骼肌D2在正常条件下和代谢应激期间的生理作用。此外，我们将与耶鲁大学小鼠代谢表型中心的Jason Kim博士合作，确定D2诱导对体内葡萄糖稳态的影响。这些研究将为候选人提供广泛的分子生物学技术方面的经验。他将成为甲状腺激素作用方面的专家，同时在能量和新陈代谢领域获得宝贵的经验，为他继续朝着成为内分泌学独立研究员的方向发展做好准备。