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Growth Hormone Signaling to the Nucleus

生长激素向细胞核发出信号

基本信息

批准号：
7992528
负责人：
Jessica Schwartz
金额：
$ 4.56万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-01-01 至 2010-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7992528
关键词：
Acetylation Acquired Immunodeficiency Syndrome Address Affect Binding Biological Models Burn injury Cell Nucleus Cell physiology Cells Clinic Clinical Code Complex Diabetes Mellitus Endogenous Factors Enhancers Event FOS gene Figs - dietary Gene Components Gene Expression Gene Targeting Genes Genetic Transcription Goals Grant Growth HIV Hormone Responsive Individual Insulin Insulin Resistance Laboratories Malignant Neoplasms Mediating Metabolism Modeling Modification Molecular Target Muscle Nuclear Nuclear Hormone Receptors Nucleoproteins Patients Phosphorylation Physiological Post-Translational Protein Processing Property Proteins RNA Interference Recovery Recruitment Activity Regulation Reporting Research Research Personnel Signal Pathway Signal Transduction Site Somatotrophin increased Somatotropin Therapeutic Therapeutic Uses Time Transcriptional Activation Transcriptional Regulation Wound Healing autocrine base chromatin immunoprecipitation cytokine effective therapy factor C gene repression growth hormone deficiency improved in vivo insight peptide hormone programs promoter response transcription factor wasting

项目摘要

Growth hormone (GH) exerts profound physiological effects on growth and metabolism, and is implicated in insulin resistance and possibly cancer. Many responses to GH depend on its ability to regulate gene transcription. We hypothesize that GH-regulated transcription is mediated by the ordered assembly of multicomponent nucleoprotein complexes on target genes and that GH- induced modifications of critical proteins can direct them into and out of the complexes. Our approach is to dissect the assembly of the multicomponent complexes in response to GH using chromatin immunoprecipitation (ChIP) and re-ChIP to define GH-regulated components of complexes and determine the dynamics of assembly on the model gene c-fos. In parallel, we will also examine post-translational modifications induced by GH on the transcription factor C/EBPp, which is essential for GH-stimulated transcription of c-fos. The sequence of complex assembly will be related to the timing and combinations of post-translational modifications of C/EBPp including phosphorylation, acetylation and sumoylation. When regulation of complexes by GH is determined, we will validate their functional importance for GH-regulated gene expression in vivo. Relevance: GH is used for treatment of short stature in GH deficiency. The anabolic properties of GH are being used therapeutically to improve wound healing and to reverse wasting in HIV patients. However, GH is also diabetogenic and reduces sensitivity to insulin. Recently, the GH- IGF axis has been implicated in cancer, broadening our need to understand the basis of GH action. The proposed studies will provide fundamental information about how GH alters cell function by regulating genes. With this information, we can identify new molecular targets to develop more effective therapies for conditions responsive to GH and to avoid GH-related complications in conditions such as diabetes and cancer.

生长激素(GH)对生长和新陈代谢有深刻的生理影响，是与胰岛素抵抗和可能的癌症有牵连。对生长激素的许多反应取决于它的能力调节基因转录。我们假设GH调节的转录是由多组分核蛋白复合体在靶基因上的有序组装和GH- 关键蛋白质的诱导修饰可以引导它们进入和离开复合体。我们的方法是使用以下方法来剖析响应GH的多组分复合体的组装染色质免疫沉淀(CHIP)和再芯片鉴定生长激素调节成分并测定了模型基因c-fos上的组装动力学。同时，我们将还研究了生长激素对转录因子C/EBPp的翻译后修饰，这是生长激素刺激c-fos转录所必需的。复杂组装序列将与C/EBPp翻译后修改的时间和组合有关，包括磷酸化、乙酰化和总甲基化。当确定GH对络合物的调节时，我们将在体内验证它们在生长激素调节基因表达中的功能重要性。相关性：生长激素用于治疗生长激素缺乏症的矮小。的合成代谢特性生长激素正被用于治疗，以促进伤口愈合和扭转艾滋病毒的消退病人。然而，GH也是糖尿病的诱因，降低了对胰岛素的敏感性。最近，GH- 胰岛素样生长因子轴与癌症有关，扩大了我们了解生长激素作用基础的需要。拟议的研究将提供生长激素如何通过以下方式改变细胞功能的基本信息调节基因。有了这些信息，我们就可以识别新的分子靶点来开发更多对生长激素反应性疾病和避免生长激素相关并发症的有效治疗糖尿病和癌症等疾病。