Creation and characterization of GH binding protein gene disrupted mice

描述（由申请人提供）：迄今为止，生长激素结合蛋白（GHBP）的生物学作用在很大程度上仍然未知。虽然已经提出了许多理论，但没有直接证据可以确定这种蛋白质的特定作用。我们和其他人认为GHBP极有可能在GH/IGF- 1轴中发挥重要作用。对此的主要论点是由于哺乳动物中产生相同蛋白质的两种不同机制的趋同进化（即，在人类中，GHBP是通过GH受体（GHR）细胞外结构域的蛋白水解裂解产生的，而在啮齿动物中，GHBP是通过GHR前体mRNA的选择性剪接产生的）。因此，我们认为阐明GHBP功能的最佳方法是创建GHBP基因特异性破坏或“敲除”小鼠系。因此，本研究的目的是创建第一个GHBP特异性基因破坏小鼠，然后确定GHBP对这些动物的生长表型以及其他代谢过程的贡献。我们实验室已经破坏了小鼠GHR/BP基因，并产生了GHR/GHBP联合“敲除”小鼠。在纯合子状态下，这些小鼠表现出侏儒表型，并作为人类生长激素不敏感状态（称为Laron综合征）的模型。虽然这些老鼠又矮又胖，但它们对胰岛素的作用非常敏感，对糖尿病肾损伤有抵抗力，而且令人惊讶的是，它们的寿命很长。有了这种动物提供的背景，我们现在准备使用靶向基因破坏方法，通过分离的GHBP基因缺陷来测试关于GHBP在体内重要性的特定假设。我们相信，一旦GHBP基因破坏小鼠产生，除了提出新的问题外，关于GHBP生物学作用的许多问题将得到解答。本研究旨在阐明生长激素结合蛋白（GHBP）的作用，这种蛋白除了在血液中结合生长激素（GH）的能力外，其功能在很大程度上仍然未知。与GHBP不同的是，生长激素的功能已经确定，并且已知生长激素在正常代谢和糖尿病、癌症甚至衰老等几种疾病的进展中发挥重要作用。因此，从这一建议中获得的结果不仅可以进一步加深我们对生长激素的理解，而且可以帮助我们进一步了解复杂的代谢状况和衰老过程。

DESCRIPTION (provided by applicant): To date, the biological role of growth hormone binding protein (GHBP) remains largely unknown. While many theories have been put forth, there is no direct evidence that can identify a specific role for this protein. We and others believe that it is highly likely that the GHBP plays a significant role in the GH/IGF- 1 axis. The main argument for this is due to the convergent evolution of two distinct mechanisms in mammals to produce the same protein (i.e. in humans the GHBP is produced by proteolytic cleavage of the GH receptor (GHR) extracellular domain while in rodents GHBP is produced by alternative splicing of the GHR precursor mRNA). Thus, we believe that the best way to elucidate the function of the GHBP is to create a GHBP gene specific disrupted or "knockout" mouse line. Hence, the objective of this research is to create the first GHBP specific gene-disrupted mouse and then to determine the contributions of GHBP on the growth phenotype as well as other metabolic processes in these animals. Our laboratory has already disrupted the mouse GHR/BP genes and generated combined GHR/GHBP "knockout" mice. In the homozygous state, these mice display a dwarf phenotype and serve as a model for a human GH- insensitive state termed Laron Syndrome. Although these mice are dwarf and obese, they are extremely sensitive to the action of insulin, resistant to diabetic kidney damage and, surprisingly, they have an extended life span. With this animal providing a background, we are now ready to test the specific hypotheses concerning the in vivo importance of GHBP by isolated GHBP gene-deficiency using a targeted gene disruption approach. We are confident that many questions concerning the biological role of GHBP will be answered in addition to new questions being raised once the GHBP gene disrupted mouse is generated. This proposal seeks to elucidate the role of growth hormone binding protein (GHBP), a protein whose function remains largely unknown other than its ability to bind growth hormone (GH) in the blood. Unlike GHBP, the function of GH is well established and GH is known to play an important role in normal metabolism and in the progression of several diseases such as diabetes, cancer and even aging. Thus, results obtained from this proposal would not only further our understanding of GH, but could help further our understanding of complex metabolic conditions and of the processes involved in aging.