Transgenic models of transmissible spongiform encephalopathy

传染性海绵状脑病的转基因模型

• 批准号: 7365119
• 负责人: MICHAEL B OLDSTONE
• 金额: $ 39.15万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7365119
• 关键词: Address; Animals; Antibodies; Appearance; Awareness; Blood; Bos taurus; Bovine Spongiform Encephalopathy; Cattle; Data; Deer; Disease; Doxycycline; Encephalopathies; Europe; Excision; Failure; Farming environment; Food Chain; Functional disorder; Human; Incidence; Modeling; Mouse Strains; Mus; Neurodegenerative Disorders; Prion Diseases; Prions; Reporting; Ruminants; Scrapie; Site; Staging; System; Tail; Testing; Tetanus Helper Peptide; Time; Transgenic Model; Transgenic Organisms; United Kingdom; design; glycosylation; in vivo; mouse model; promoter; reconstitution; small molecule; transmission process

DESCRIPTION (provided by applicant): Transmissible spongiform encephalopathy (TSE) or prion diseases are rare fatal neurodegenerative illnesses of humans and other animals. The recent awareness of TSE diseases has accelerated due to the appearance of bovine encephalopathy or mad cow disease in Europe, especially the United Kingdom, and its potential for transmission via the food chain to humans and the awareness that the majority of deer and elk on farms as well as 10 to 20% of wild deer and about 1 % of elk develop TSE disease (CWD). The transmission of CWD to humans is unknown and although there is currently no evidence of passage of TSE via blood products in humans exposed to BSE, the reported transmission by blood in ruminants is of concern. Our hypothesis is that uniquely designed and developed transgenic (tg) models offer the opportunity to address important but as yet unknown or unresolved issues in TSE diseases. Towards that end we have successfully developed a tg model using PrP ko mice as a host in which expression of PrPsen can be induced in a rev tet system with administration of doxycycline, and a tg model in which GP1 anchorless PrPsen is also expressed in other PrP ko mice. The former will allow data on the turnover of PrPres in vivo and provide information as to its removal, information of value to determine the potential efficacy of anti-PrP therapy during different timed stages of disease. The latter GP1-/- model should provide data on glycosylation, spread or failure to spread PrPres from the inoculated site, the ability of GP1 anchorless PrPsen to be converted to PrPres to cause disease, as well as analysis of potential differences in incubation time/disease incidence among different strains of mouse scrapie. The third tg model is the expression of white tail deer (WTD) prion under control of the mouse PrP promoter in PrP ko mice, This model should be useful to study pathophysiology of CWD as well as probing CWD strain differences. These studies will be complimented by providing the appropriate PrP ko and PrP reconstituted mice for studies by Jose Criado and mouse models to test efficacy of both antibody and small molecules that mimic antibody in treatment of TSE.

描述（由申请人提供）：可传播的海绵状脑病（TSE）或Prion 疾病是人类和其他动物的罕见致命神经退行性疾病。最近 由于欧洲，尤其是英国的牛脑病或疯牛病的出现，对TSE疾病的认识加速了，及其通过食物链传播到人类以及大多数在农场上的鹿和麋鹿的潜力，以及大多数在农场上的鹿和麋鹿，以及野生鹿以及大约1％的野生鹿以及大约1％的Elk Depere（CWD）（CWD）。 CWD向人类的传播尚不清楚，尽管目前尚无证据表明通过暴露于BSE的人类通过血液产物通过血液产物通过，但引起反刍动物的血液传播是令人关注的。我们的假设是，唯一设计和开发的转基因（TG）模型提供了解决重要但尚未解决或未解决的TSE疾病问题的机会。为此，我们成功地使用了PRP KO小鼠作为宿主开发了TG模型，其中可以在Rev Tet系统中诱导Prpsen的表达，并使用强力霉素给药，而TG模型也可以在其他PRP KO小鼠中表达GP1锚定prpsen。前者将允许有关营业额的数据 Prpres in Vivo，并提供有关其去除的信息，以确定疾病不同定时阶段抗PRP治疗的潜在疗效的价值信息。后者的GP1 - / - 模型应提供有关糖基化，扩散或未能从接种部位传播PRPRE的数据，GP1锚定PRPSEN转化为PRPRES引起疾病的能力，以及分析小鼠擦皮不同菌株中孵化时间/疾病发生率的潜在差异。第三个TG模型是在PRP KO小鼠中控制小鼠PRP启动子的白尾鹿（WTD）prion的表达，该模型对于研究CWD的病理生理学以及探测CWD菌株差异应该很有用。这些研究将通过为Jose Criado和小鼠模型提供适当的PRP KO和PRP重构小鼠进行研究来补充这些研究，以测试模仿TSE治疗的抗体和小分子的疗效。