MURINE MODEL FOR HEPATITIS C VIRUS INVESTIGATIONS

本研究的目的是建立一个人类免疫缺陷的小鼠模型。 丙型肝炎病毒（HCV）研究。免疫抑制小鼠系， 人类组织的耐受性植入已成功用于 其他人类病毒病原体的研究。研究者建议 确定两种新开发的小鼠品系用于 HCV研究第一个是NOD/scid小鼠，由C.B-17杂交产生 具有非肥胖糖尿病品系的SCID小鼠。所得到的NOD/scid小鼠 已被证明是用于人类移植的上级模型。 淋巴组织和人类嗜淋巴病毒的研究。初步 在实验中，申请人已经证明NOD/scid小鼠可以是 用作HCV研究的模型。NOD/scid小鼠接种人 胎肝细胞悬液导致持续的人淋巴细胞 移植细胞悬液与人的移植前孵育 含高滴度HCV的血清导致持续的HCV感染， 小鼠（6个月），通过检测HCV RNA和 抗原尽管观察到这一点，人肝细胞移植在这些 小鼠是有限的。在另一种小鼠模型中， 尿激酶型组织型纤溶酶原激活物的表达与 白蛋白启动子（Alb-uPA小鼠）已被证明接受异种基因 肝细胞移植申请人将使用交叉 NOD/scid/Alb-uPA小鼠作为人胎肝细胞受体的研究 移植，并研究这些小鼠的能力，以支持 持续和生产性HCV感染。 候选人，大卫奥达奇，是一个董事会认证的内科医生和传染病 从事三年分子病毒学研究的疾病专家 体验.他在同行评审期刊上发表过文章， 他在国家和国际会议上的丙型肝炎病毒研究。 这项申请的资金将支持他过渡到一个完全 独立调查员，特别是支持他，而他获得 免疫学领域的培训。本文中描述的研究 该提案将在加内特博士的共同赞助下进行 凯尔索是公认的鼠免疫遗传学和免疫学权威， 和分子病毒学领域的专家罗伯特·罗威尔博士， 在疾病动物模型的开发方面具有丰富的经验。

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.