The Role of Glucocorticoids in Cell Fate Determination

描述（由申请人提供）： 本研究的目的是探讨糖皮质激素（GC）如何调节多能细胞向脂肪细胞的分化，以及GC调节基因myostatin在指导这一过程中的作用。长期目标是了解GC如何通过其受体（GR）影响细胞命运决定和分化。GC已被用于治疗性诱导广泛的细胞类型的分化，包括胎儿中的早产儿肺组织和未成熟的恶性肿瘤，如白血病和神经母细胞瘤。GC还被用作治疗广泛的医学病症，包括移植排斥、哮喘、类风湿性关节炎和其他自身免疫性疾病。有趣的是，GC过量的副作用与胰岛素抵抗和代谢综合征的体征和症状有显著重叠。然而，GC活性和代谢综合征的发展之间的直接联系尚未阐明。本研究的目的是检验这一假设，即参与GC调节细胞命运决定和分化程序的相同途径可能有助于GC过量患者中发现的一些副作用的发展，如肥胖和胰岛素抵抗。总体目标是了解GC如何调节细胞命运以及该途径在生理学和疾病中的作用。该项目将集中于GC靶基因（肌肉生长抑制素）的调控以及这种调控对细胞命运决定、脂肪形成和胰岛素敏感性的影响。有三个具体目标：（1）研究多能间充质细胞中GC对肌生长抑制素的调节，以评估对细胞命运决定的影响，（2）分析GR和肌生长抑制素在体内脂肪形成中的作用，和（3）评估GR在脂肪细胞分化中的作用和在GC相关疾病的病理生理学变化中的作用，并确定肌生长抑制素是否与GR在这些疾病中的作用相关。该项目将使用分子生物学技术和转基因小鼠模型，包括转基因和基因敲除，以阐明GC调节肌肉生长抑制素的机制，重点是脂肪细胞的命运。这项研究将提供深入了解GC治疗的衰弱副作用的原因，数百万人患有。此外，它将阐明GC作用的机制，这对理解糖尿病等疾病的发展具有重要意义。

DESCRIPTION (provided by applicant): The goal of this research is to investigate how glucocorticoids (GCs) regulate the differentiation of pluripotent cells into adipocytes and the role of myostatin, a GC regulated gene, in directing this process. The long term objectives are to understand how GCs, acting via their receptor (GR), influence cell fate determination and differentiation. GCs have been used to therapeutically induce differentiation of a broad range of cell types including premature lung tissue in the fetus and immature malignancies such as leukemia and neuroblastoma. GCs have also been used as therapy for a wide range of medical conditions including transplant rejection, asthma, rheumatoid arthritis and other autoimmune diseases. Interestingly, the side effects of GC excess have a signifcant overlap with the signs and symptoms of insulin resistance and the metabolic syndrome. However, a direct connection between GC activity and the development of the metabolic syndrome has yet to be elucidated. The aim of this study study is to examine the hypothesis that the same pathways involved in GC regulation of cell fate determination and differentiation programs may contribute to the development of some of the side effects found in patients with GC excess such as obesity and insulin resistance. The overall goal is to understand how GCs regulate cell fate and the role this pathway plays in both physiology and disease. This project will focus on the regulation of a GC target gene (myostatin) and the implications of this regulation on: cell fate determination, adipogenesis and insulin sensitivity. There are three specific aims: (1) to investigate the regulation of myostatin by GCs in pluripotent mesenchymal cells in order to assess the effect on cell fate determination, (2) to analyze of the role of GR and myostatin in adipogenesis in vivo, and (3) to evaluate the role of GR in adipocyte differentiation and in the pathophysiological changes in GC related diseases and determine if myostatin is relevant to GR's role in these diseases. This project will use molecular biology techniques and genetically modified mouse models, including transgenics and knock-outs, to elucidate the mechanisms by which GCs regulate myostatin with a focus on adipocyte cell fate. This research will provide insight into the cause of the debilitating side effects of GC therapy that millions of people suffer from. In addition, it will shed light on the mechanisms of GC action which has important implications for understanding the development of diseases such as diabetes.