Molecular Genetics Of Scrapie Pathogenesis

传染性海绵状脑病（tse或朊病毒病）是一类罕见的神经退行性疾病，包括人类克雅氏病（CJD）、绵羊痒病、牛海绵状脑病（BSE）和长尾鹿和麋鹿的慢性消耗性疾病（CWD）。TSE传染性可以跨越物种屏障。BSE在英国感染人类的事实，以及CWD可能在美国发生类似行为的担忧，强调了了解TSE发病机制和开发有效治疗方法的重要性。TSE疾病的传染因子被称为朊病毒，主要由正常的、蛋白酶敏感的朊病毒蛋白（PrP-sen）的一种异常折叠的、蛋白酶抗性的形式（PrP-res或PrPSc）组成。PrP-sen和PrP-res之间的氨基酸同源性可能影响对感染的易感性，而PrP-res分子之间的结构差异被认为编码菌株表型。我的研究涉及朊病毒疾病在分子和致病水平上的许多不同方面。特别是，我的实验室专注于：1)确定在朊病毒感染期间发生的最早事件，2)精确定义发生PrP-res的不同细胞区室，3)确定朊病毒株的分子基础，4)开发有效的朊病毒治疗方法。

Transmissible spongiform encephalopathies (TSEs or prion diseases) are a group of rare neurodegenerative diseases which include Creutzfeldt-Jakob disease (CJD) in humans, scrapie in sheep, bovine spongiform encephalopathy (BSE) and chronic wasting disease (CWD) in mule deer and elk. TSE infectivity can cross species barriers. The fact that BSE has infected humans in Great Britain and concerns that CWD may act similarly in the US underscores the importance of understanding TSE pathogenesis and developing effective therapeutics. The infectious agent of TSE diseases is called a prion and is largely composed of an abnormally refolded, protease resistant form (PrP-res or PrPSc) of the normal, protease-sensitive prion protein, PrP-sen. Susceptibility to infection can be influenced by amino acid homology between PrP-sen and PrP-res while differences in structure between PrP-res molecules are believed to encode strain phenotypes. My studies address many different aspects of prion diseases at both the molecular and pathogenic level. In particular, my laboratory focuses on: 1) identifying the earliest events which occur during prion infection, 2) precisely defining the different cellular compartments where PrP-res formation occurs, 3) determining the molecular basis of prion strains and, 4) development of effective prion therapeutics. In vitro, infection of mouse scrapie-positive cells with the Moloney murine leukemia retrovirus can enhance the spread and release of mouse scrapie infectivity. These data suggested that co-infection of a prion-infected individual with a retrovirus could lead to exacerbation of prion disease. In 2012, we studied how retroviral co-infection influenced the progression of prion disease. Our results show that the murine leukemia virus Friend (F-MuLV) enhanced the release and spread of scrapie infectivity in cell culture but did not affect the pathogenesis of prion disease in vivo. This work was published in 2012 in PLoS One. In 2012, we completed in vivo work for the initial studies analyzing acute prion infection following sciatic nerve inoculation in mice. Based on those results, we have expanded the study to look at early events during prion infection following intracranial inoculation. We are also continuing in vitro studies begun last year aimed at characterizing the interaction of PrP-res with the cell during the initial stages of both mouse and human prion infection. Finally, in 2012 we completed a long-term collaborative project with Dr. Michael Oldstone assaying for prion infectivity in formalin-fixed paraffin embedded human brain and heart tissue from CJD and non-CJD patients. We anticipate that these data will be submitted for publication before the end of 2012.