Aging Disease--Prion/Transgenic/Immunologic Studies

衰老疾病--朊病毒/转基因/免疫学研究

基本信息

批准号：
7365123
负责人：
MICHAEL B OLDSTONE
金额：
$ 149.49万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-12-01 至 2009-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7365123
关键词：
Aging Disease Prion Transgenic Immunologic

项目摘要

DESCRIPTION (provided by applicant): Transmissible spongiform encephalopathies (TSE) are degenerative brain diseases that occur in primates and ruminants, and include scrapie in sheep, bovine spongiform encephalopathy (BSE) and several human diseases such as Creutzfeldt-Jakob disease, Kuru, fatal familial insomnia and Gerstmann-Straussler-Scheinker syndrome. Recent evidence indicates transmission of BSE across species barrier to humans resulting in a distinct Creutzfeldt-Jakob disease (vCJD). Although roughly only 130 cases of vCJD have occurred, several million persons including over 3 million Americans have been exposed to meat from contaminated BSE cows. The long incubation period of TSE disease suggests this may turn out to be a major health problem in the future. Prion protein (PrP) plays an essential role in TSE disease as the presence of both the normal PrP (PrPsen) and the abnormal prbtease resistant PrP (PrPres) is required for disease associated with TSE. This Program Project is designed to test the hypothesis that antibodies directed to PrP can both map the structure of the molecule and act to prevent the conversion of PrPsen to PrPres. These antibodies and small molecules that mimic their interaction with PrP may be useful both as diagnostic markers and therapies. Anthony Williamson who, with Dennis Burton, developed recombinant phage antibodies to PrP will continue to obtain and clone novel anti-PrP antibodies and use these reagents to study function-structure of PrP. Dennis Burton will focus primarily on study of PrP antibody-PrP interactions in order to develop small molecules that can pass the blood-brain-barrier. Michael Oldstone will continue to generate novel transgenic mouse models designed to analyze PrP turnover, role of GP1 anchor of PrP and use models that shorten the incubation time to develop TSE to test the efficiency of the antibodies and small mimicking molecules designed by Williamson and Burton, respectively. Lastly, Jose Criado will continue his electrophysiology and behavioral studies on the normal function of PrP and on its aberrations during TSE disease.

描述（由申请人提供）：可传播的海绵状脑病（TSE）是在灵长类动物和反刍动物中发生的退化性脑部疾病，包括羊中的小虫，牛海绵状脑病（BSE）以及几种人类疾病以及几种人为疾病Gerstmann-Straussler-Scheinker综合征。最近的证据表明，BSE跨物种障碍传播到人类，导致了明显的克鲁特兹菲尔特 - 贾科布疾病（VCJD）。尽管发生了大约130例VCJD案件，但包括超过300万美国人在内的数百万人受到了受污染的BSE奶牛的肉类暴露。 TSE疾病的漫长孵化期表明，这可能是将来的主要健康问题。 Prion蛋白（PRP）在TSE疾病中起着至关重要的作用，因为与TSE相关的疾病需要正常的PRP（PRPSEN）和抗PRBTease抗性PRP（PRPRP）异常。该程序项目旨在检验以下假设：针对PRP的抗体既可以绘制分子的结构，又可以绘制以防止Prpsen转化为PRPRES的抗体。这些模仿它们与PRP相互作用的抗体和小分子可能是诊断标记和疗法的用途。安东尼·威廉姆森（Anthony Williamson）与丹尼斯·伯顿（Dennis Burton）一起开发了对PRP的重组噬菌体抗体，将继续获得并克隆新颖的抗PRP抗体，并使用这些试剂来研究PRP的功能结构。丹尼斯·伯顿（Dennis Burton）将主要关注PRP抗体PRP相互作用的研究，以开发可以通过血脑屏障的小分子。迈克尔·奥尔德斯通（Michael Oldstone）将继续生成新型的转基因小鼠模型，旨在分析PRP周转，PRP的GP1锚作用，并使用模型缩短了孵育时间以开发TSE以测试Williamson和Burton设计的抗体和小模仿分子的效率。最后，何塞·克里亚多（Jose Criado）将继续他的电生理学和行为研究，涉及PRP的正常功能及其在TSE疾病期间的畸变。

项目成果

期刊论文数量（58）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Anatomy of viral persistence: mechanisms of persistence and associated disease.

DOI：
10.1016/s0065-3527(08)60075-5
发表时间：
1996
期刊：
Advances in virus research
影响因子：
0
作者：
J. Torre;Michael B. A. Oldstone
通讯作者：
J. Torre;Michael B. A. Oldstone

Viruses as therapeutic agents. II. Viral reassortants map prevention of insulin-dependent diabetes mellitus to the small RNA of lymphocytic choriomeningitis virus.

病毒作为治疗剂。

DOI：
10.1084/jem.171.6.2091
发表时间：
1990
期刊：
The Journal of experimental medicine
影响因子：
0
作者：
Oldstone,MB;Ahmed,R;Salvato,M
通讯作者：
Salvato,M

Lack of prion infectivity in fixed heart tissue from patients with Creutzfeldt-Jakob disease or amyloid heart disease.

克雅氏病或淀粉样心脏病患者的固定心脏组织中缺乏朊病毒感染性。

DOI：
10.1128/jvi.00692-13
发表时间：
2013
期刊：
Journal of virology
影响因子：
5.4
作者：
Priola,SuzetteA;Ward,AnneE;McCall,ShermanA;Trifilo,Matthew;Choi,YoungPyo;Solforosi,Laura;Williamson,RAnthony;Cruite,JustinT;Oldstone,MichaelBA
通讯作者：
Oldstone,MichaelBA

Cytotoxic T lymphocytes do not control lymphocytic choriomeningitis virus infection of BB diabetes-prone rats.

细胞毒性 T 淋巴细胞不能控制 BB 糖尿病倾向大鼠的淋巴细胞性脉络膜脑膜炎病毒感染。