Transgenic models of transmissible spongiform encephalopathy

传染性海绵状脑病的转基因模型

• 批准号: 7569316
• 负责人: MICHAEL B OLDSTONE
• 金额: $ 37.37万
• 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/7569316
• 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）：传染性海绵状脑病（TSE）或朊病毒 疾病是人类和其他动物罕见的致命性神经退行性疾病。最近的 由于牛脑病或疯牛病在欧洲（尤其是英国）的出现，以及其通过食物链传播给人类的潜力，以及人们认识到农场中的大多数鹿和麋鹿也有可能感染 TSE 疾病，人们对 TSE 疾病的认识有所提高。 10% 至 20% 的野鹿和约 1% 的麋鹿患有 TSE 疾病 (CWD)。 CWD 向人类的传播情况尚不清楚，尽管目前没有证据表明 TSE 通过暴露于 BSE 的人类的血液制品传播，但报道的反刍动物通过血液传播的情况值得关注。我们的假设是，独特设计和开发的转基因 (tg) 模型提供了解决 TSE 疾病中重要但尚未未知或未解决的问题的机会。为此，我们成功开发了一种使用 PrP ko 小鼠作为宿主的 tg 模型，其中可以通过给予多西环素在 rev tet 系统中诱导 PrPsen 的表达，以及 GP1 无锚定 PrPsen 也在其他 PrP 中表达的 tg 模型老鼠啊。前者将允许提供有关营业额的数据 PrPres 体内并提供有关其去除的信息，这些信息对于确定抗 PrP 治疗在疾病不同时间阶段的潜在功效具有价值。后一个 GP1-/- 模型应提供有关糖基化、PrPres 从接种位点传播或传播失败的数据、GP1 无锚定 PrPsen 转化为 PrPres 导致疾病的能力，以及孵化时间/潜在差异的分析不同品系小鼠痒病的发病率。第三个tg模型是在PrP ko小鼠中受小鼠PrP启动子控制的白尾鹿(WTD)朊病毒的表达。该模型对于研究CWD的病理生理学以及探索CWD菌株差异应该是有用的。这些研究将通过提供适当的 PrP ko 和 PrP 重组小鼠供 Jose Criado 和小鼠模型进行研究来补充，以测试抗体和模拟抗体的小分子在 TSE 治疗中的功效。