Targeted Overexpression of PTH-related Peptide

PTH相关肽的靶向过表达

• 批准号: 6823184
• 负责人: Arthur Eastwood Broadus
• 金额: $ 30.17万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-04-16 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6823184
• 关键词: biological signal transduction; gene deletion mutation; gene expression; gene targeting; genetic models; genetically modified animals; hippocampus; hormone regulation /control mechanism; laboratory mouse; model design /development; nervous system regeneration; neuroendocrine system; neuroprotectants; neuroregulation; osteogenesis; parathyroid hormone related protein; spinal ganglion

DESCRIPTION (provided by applicant): PTHrP was discovered in the late 1980s as the mediator of the syndrome of humoral hypercalcemia of malignancy, and it was at that time a molecule in search of a function. One PTHrP function is as a developmental regulatory molecule. The best defined such effects are in endochondral bone formation, the eruption of teeth, and formation of the mammary epithelium. In adults, PTHrP functions as a mechanically-induced product in smooth muscle structures throughout the organism. For the past several years, our group has focused on PTHrP in other excitable cells, and we propose here four projects to further our understanding of these potential functions. Two of these projects (3 and 4) are entirely new initiatives. Aim 1 is to create a lacZ PTHrP knock-in by homologous recombination. This project is at the blastocyst-injection stage. This allele will provide a PTHrP gene readout in physiological regulation and in conditional deletion experiments. Aim 2 is to create models that will enable study of the potential role of PTHrP as a neuroprotective peptide. One subaim will be to conditionally delete PTHrP from a CA3 subfield of the hippocampus via a kainite receptor-driven Cre and a second subaim to delete PTHrP from the CA1 subfield by an inducible calmodulin kinase-driven Cre. Subaim 3 is create models that will enable study of PTHrP involvement in neuronal regeneration, based on preliminary evidence in vitro that suggests such a function. One subaim will be to delete PTHrP in peptidergic primary sensory neurons of the dorsal root ganglia and a second to delete PTHrP in epidermal structures via an inducible Cre-targeting system. These models will focus on potential PTHrP functions in DRG and cutaneous nerve regeneration, respectively. Aim 4 will focus on the potential role of PTHrP in mechanical-regulated bone formation in vivo. This aim too is based on preliminary evidence of such an effect in vitro. The model to be created will be a collagen gene-driven Cre under the control of PR1 (RU-486).

描述(申请人提供)：甲状旁腺素受体是20世纪80年代末被发现的恶性肿瘤体液高钙血症综合征的介质，当时它是一个寻找功能的分子。PTHrP的一个功能是作为发育调节分子。最明确的作用是软骨内骨的形成、牙齿的萌出和乳腺上皮的形成。在成人中，PTHrP作为机械诱导的产物在整个生物体的平滑肌肉结构中发挥作用。在过去的几年里，我们的团队一直专注于其他可兴奋细胞中的PTHrP，我们在这里提出四个项目来加深我们对这些潜在功能的理解。其中两个项目(3和4)是全新的举措。 目的1是通过同源重组构建LacZ PTHrP敲入基因。该项目正处于囊胚注射阶段。该等位基因将在生理调节和条件性缺失实验中提供PTHrP基因读出。 目标2是建立能够研究PTHrP作为神经保护肽的潜在作用的模型。一个子目标是通过海人藻酸钾受体驱动的Cre有条件地从海马区CA3亚区删除PTHrP，第二个子目标是通过可诱导的钙调蛋白激酶驱动的Cre从CA1亚区删除PTHrP。 Subaim 3正在建立模型，基于体外初步证据表明PTHrP参与神经元再生，从而能够研究这种功能。一个子目标是删除背根神经节中的肽能初级感觉神经元中的PTHrP，第二个子目标是通过可诱导的CRE靶向系统删除表皮结构中的PTHrP。这些模型将分别关注PTHrP在DRG和皮神经再生中的潜在作用。 目的4重点介绍PTHrP在体内机械调控骨形成中的潜在作用。这一目标也是基于体外实验中存在这种效应的初步证据。所要建立的模型将是在PR1(RU-486)控制下的胶原基因驱动的Cre。