The Role of Glucocorticoids in Cell Fate Determination

糖皮质激素在细胞命运决定中的作用

• 批准号: 7141363
• 负责人: Brian J Feldman
• 金额: $ 12.79万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7141363
• 关键词: adipocytes; adipose tissue; cell differentiation; genetically modified animals; glucocorticoids; insulin sensitivity /resistance; laboratory mouse; myostatin; pluripotent stem cells; tissue /cell culture

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.

描述（由申请人提供）： 这项研究的目的是研究糖皮质激素（GCS）如何调节多能细胞的分化为脂肪细胞，以及GC调节基因肌抑制素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）作用，影响细胞命运的确定和分化。 GC已被用于治疗诱导广泛的细胞类型的分化，包括胎儿中的肺部过早组织以及白血病和神经母细胞瘤等未成熟恶性肿瘤。 GC也已被用作多种医疗状况的治疗，包括移植排斥，哮喘，类风湿关节炎和其他自身免疫性疾病。有趣的是，GC多余的副作用与胰岛素抵抗和代谢综合征的体征和症状具有明显的重叠。但是，GC活性与代谢综合征的发展之间的直接联系尚未阐明。这项研究的目的是检查以下假设：细胞命运确定和分化程序中涉及的相同的途径可能有助于发展GC过量患者（例如肥胖和胰岛素抵抗）的某些副作用。总体目标是了解GC如何调节细胞命运以及该途径在生理和疾病中的作用。该项目将重点介绍GC靶基因（肌生抑素）的调节及其对：细胞命运确定，脂肪生成和胰岛素敏感性的影响。 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与GR在这些疾病中的作用有关。该项目将使用分子生物学技术和转基因的小鼠模型，包括转基因和敲除，以阐明GCS调节肌抑制素的机制，重点是脂肪细胞细胞的命运。这项研究将洞悉数百万人遭受的GC治疗的副作用的原因。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。