STEROID AND GROWTH FACTOR CONTROL OF DIFFERENTIATION

类固醇和生长因子控制分化

• 批准号: 3273334
• 负责人: GORDON M RINGOLD
• 金额: $ 16.52万
• 依托单位: AFFYMAX RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-12-01 至 1996-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3273334
• 关键词: adipocytes; binding proteins; biological signal transduction; cell differentiation; fibroblast growth factor; gene expression; genetic mapping; genetic promoter element; genetic recombination; genetic regulatory element; genetic transcription; glucocorticoids; growth factor; growth inhibitors; hormone regulation /control mechanism; immunochemistry; molecular cloning; nucleic acid sequence; platelet derived growth factor; radiotracer; transcription factor; tumor necrosis factor alpha

The ability of specific hormones to influence developmental processes has been amply documented, however, the analysis of underlying mechanisms has been severely compromised by the complexity of the systems being studied and the difficulty in obtaining pure populations of cells that undergo differentiation under controlled conditions. Moreover, those of us interested in vertebrate systems have not had the benefit of genetic approaches to help in dissecting the complex regulatory networks that dictate the timing and implementation of developmental decisions. In somewhat anthropomorphic terms, the central theme of this proposal surrounds the following question. What are the biochemical signals that instruct "determined" cells to not express differentiated functions at inappropriate times and (2) how does the cell sense the environmental cues that instruct it to activate a specified set of tissue-specific genes? It is the nature of this triggering process and the roles that various classes of hormones play in regulating the decision to differentiate that is the focus of our studies. Specifically, we will pursue studies aimed at understanding the mechanisms by which: 1) glucocorticoid hormones accelerate the differentiation of adipogenic cells and 2) certain growth factors (notable FGF and PDGF) prevent differentiation. Major emphasis will be placed on characterizing the regulation and the function of the glucocorticoid-inducible and FGF/PDGF-repressible AP27 gene, the product of which appears to play a key role in triggering the differentiation of TA1 and 3T3-L1 adipocytes. In addition we will attempt to delineate the cis-acting elements and transcription factors that are crucial for regulating the expression of a gene (clone 47/FSP27) that is transcriptionally activated only in differentiated adipocytes. It is among these regulatory factors that we imagine the targets(s) for the hormonal signals ultimately reside. Our goal is to elucidate the pathways that hormonal signals utilize to alter the ability of cells to undergo differentiation. Complex interactions between the growth state of the cell and such hormonal signals will play a prominent role in our studies. We anticipate that the approaches we are taking will help to elucidate fundamental aspects of tissue-specific gene expression, the biochemistry of cell differentiation, and the regulatory networks established by hormonal signal

特定激素影响发育过程的能力 然而，已经有大量的文献记载， 机制已严重损害了复杂的 系统的研究和获得纯种群的困难 在受控条件下进行分化的细胞。 此外，我们这些对脊椎动物系统感兴趣的人还没有 遗传学方法的好处，以帮助解剖复杂的 规定时间和实施的监管网络 发展决策。 从某种拟人化的角度来看，这一建议的中心主题 围绕着下面的问题。 是什么生化信号 指示“确定的”细胞不表达分化功能， 不适当的时间和（2）细胞如何感知环境 指示它激活一组特定的组织特异性 基因？ 正是这一触发过程的性质和 不同种类的激素在调节 这是我们研究的重点。 具体而言，我们将继续进行旨在了解 糖皮质激素的作用机制：1）糖皮质激素加速 成脂细胞的分化和2）某些生长因子 （值得注意的是FGF和PDGF）阻止分化。 重点将是 的调节和功能的特点放在 糖皮质激素诱导和FGF/PDGF抑制的AP 27基因，该产物 其中似乎发挥了关键作用，触发分化， TA 1和3 T3-L1脂肪细胞。 此外，我们将尝试描绘 顺式作用元件和转录因子， 调节基因（克隆47/FSP 27）的表达，所述基因 仅在分化的脂肪细胞中转录激活。 是 在这些调节因素中，我们想象的目标是 荷尔蒙信号最终会存在。 我们的目标是阐明激素信号利用的途径， 改变细胞进行分化的能力。 复杂 细胞的生长状态和这种激素之间的相互作用 信号将在我们的研究中发挥重要作用。 我们预计 我们正在采取的方法将有助于阐明基本的方面， 组织特异性基因表达，细胞生物化学 分化，以及由激素信号建立的调节网络