MURINE MODEL FOR HEPATITIS C VIRUS INVESTIGATIONS

这项提议的目的是开发一种用于人类的小鼠模型 丙型肝炎病毒(HCV)研究。免疫抑制的小鼠品系 人体组织的耐受植入已成功地用于 研究其他人类病毒病原体。调查员提议 建立两个新开发的小鼠品系的潜力 丙型肝炎病毒的研究。第一种是NOD/SCID小鼠，是通过与C.B-17杂交而产生的 非肥胖糖尿病品系的SCID小鼠。由此产生的NOD/SCID小鼠 已经被证明是植入人类的一种优越模式 淋巴组织和人类淋巴营养病毒的研究。在预赛中 实验中，申请人已经证明了NOD/SCID小鼠可能是 用作丙型肝炎病毒研究的模型。人免疫NOD/SCID小鼠的实验研究 胎肝细胞悬液导致持续性人类淋巴样病变 嫁接。细胞悬液与人的移植前孵育 含高滴度丙型肝炎病毒血清导致丙型肝炎病毒持续感染 小鼠(6个月)，通过检测丙型肝炎病毒RNA和 抗原。尽管如此，人类肝细胞在这些细胞中的植入 老鼠是有限的。在另一种小鼠模型中，转基因小鼠 与尿激酶型组织型纤溶酶原激活物连锁的表达 白蛋白启动子(Alb-uPA小鼠)已被证明接受异种 肝细胞移植。申请人将利用十字交叉 NOD/SCID/Alb-uPA小鼠作为人胎肝细胞的受体 移植，并研究这些小鼠的支持能力 持续和多产的丙型肝炎病毒感染。 候选人大卫·奥达克是一名董事会认证的内科医生，具有感染力。 拥有三年分子病毒学研究经验的疾病专家 经验。他曾在同行评议的期刊上发表文章，并发表了 他在国内和国际会议上从事丙型肝炎病毒研究。 这项申请的资金将支持他过渡到完全 独立调查员，特别是在他获得 在免疫学领域的培训。这篇文章中描述的研究 该提案将在加内特博士的共同赞助下进行 Kelsoe是公认的小鼠免疫遗传学和免疫学权威， 罗伯特·罗威尔博士是分子病毒学领域的专家， 在疾病动物模型开发方面有丰富的经验。

The objective of this proposal is to develop a murine model for human hepatitis C virus (HCV) research. Immunosuppressed murine lines which tolerate engraftment of human tissues have been used successfully for the study of other human viral pathogens. The investigator proposes to establish the potential of two newly developed murine strains for the study of HCV. The first, the NOD/scid mouse, resulted from crossing C.B-17 scid mice with the non-obese diabetic strain. The resultant NOD/scid mouse has been demonstrated to be a superior model for the engraftment of human lymphoid tissue and studies of human lymphotrophic viruses. In preliminary experiments, the applicant has demonstrated that the NOD/scid mouse may be used as a model for HCV research. Inoculation of NOD/scid mice with human fetal liver cell suspensions resulted in persistent human lymphoid engraftment. Pre-transplantation incubation of cell suspensions with human serum containing high titer HCV resulted in persistent HCV infection of the mouse (6 months), demonstrated by the detection of both HCV RNA and antigens. Despite this observation, human hepatocyte engraftment in these mice was limited. In a different murine model, mice transgenic for the expression of urokinase type tissue plasminogen activator linked to the albumin promoter (Alb-uPA mice) have been demonstrated to accept xenogenic hepatocyte transplantation. The applicant will utilize crossed NOD/scid/Alb-uPA mice as recipients for human fetal liver cell transplantation, and investigate the ability of these mice to support persistent and productive HCV infection. The candidate, David Oldach, is a board certified internist and infectious disease specialist with three years of molecular virology research experience. He has published in peer-reviewed journals and has presented his hepatitis C virus research at national and international meetings. Funding of this application will support his transition to a fully independent investigator, and in particular, support him while he acquires training in the field of immunology. The research described in this proposal will be conducted under the joint sponsorship of Dr. Garnett Kelsoe, a recognized authority on murine immunogenetics and immunology, and Dr. Robert Rohwer, an expert in the field of molecular virology with extensive experience in the development of animal models for disease.