Validating a new model for growth hormone receptor activation

验证生长激素受体激活的新模型

• 批准号: nhmrc : 351584
• 负责人: Prof Michael Waters
• 金额: $ 31.51万
• 依托单位: The University of Queensland
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2005
• 资助国家: 澳大利亚
• 起止时间: 2005-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/validating-new-model-receptor-activation/78506
• 关键词: Validating; new; model; growth; hormone

Growth hormone is an important hormone therapeutic for treating dwarfism. Recently, many new therapeutic applications for growth hormone have been discovered, particularly in relation to its anabolic actions. These include post surgery recovery, enhanced bone fracture healing, Crohns disease, dilated cardiomyopathy, infertility and ageing. The hormone exerts these actions through its receptor, which is a class1 cytokine receptor, similar to many receptors important in regulating immunity, inflammation, metabolism and cancers. In principle, if we can find out how the GH receptor works, this information would help in designing drugs to treat many immune and inflammatory disorders. With current NHMRC support we have developed a model which describes how GH activates the receptor at a molecular level. The model involves two pre-associated receptors at the cell surface binding to the hormone, with the result that the receptors are rotated relative to each other, and this brings the two JAK2 signalling units attached tothe receptor inside the cell into alignment, so they can activate each other. We can activate the receptor without hormone by artificially rotating it. This model is a prediction based on several techniques, but lacks proof of rotation. There are also a number of issues relating to the need for rigidity in the receptors, so the torque can be transmitted into the cell, since many believe there is no rigidity just above the membrane. We predict there is , but need to prove this. This information is vital for designing small orally active mimics of growth hormone, and for developing GH antagonists, likely to be useful for breast and colon cancer. Finally, we have evidence that the specificity of receptor signalling can be changed by mutating the outer part of the receptor (novel). We believe this can be used to change the activity spectrum of GH, hence decrease side effects, by developing analogs which activate one pathway or the other.

生长激素是治疗侏儒症的重要激素治疗药物。最近，已经发现了生长激素的许多新的治疗应用，特别是与其合成代谢作用有关。这些包括术后恢复，骨折愈合，克罗恩病，扩张型心肌病，不孕症和衰老。这种激素通过其受体发挥这些作用，受体是一种1类细胞因子受体，类似于调节免疫、炎症、代谢和癌症的许多重要受体。原则上，如果我们能发现GH受体是如何工作的，这些信息将有助于设计治疗许多免疫和炎症疾病的药物。在目前NHMRC的支持下，我们开发了一个模型，描述了GH如何在分子水平上激活受体。该模型涉及细胞表面的两个预先关联的受体与激素结合，结果是受体相对于彼此旋转，这使得细胞内连接到受体的两个JAK2信号单元对齐，因此它们可以相互激活。我们可以通过人工旋转来激活受体，而不需要激素。这个模型是基于几种技术的预测，但缺乏旋转的证明。还有一些问题与受体中需要刚性有关，因此扭矩可以传递到细胞中，因为许多人认为膜上方没有刚性。我们预测有，但需要证明这一点。这些信息对于设计生长激素的小的口服活性模拟物和开发可能对乳腺癌和结肠癌有用的GH拮抗剂是至关重要的。最后，我们有证据表明，受体信号的特异性可以通过突变受体的外部来改变（新颖）。我们相信这可以用来改变GH的活性谱，从而减少副作用，通过开发激活一种途径或另一种途径的类似物。