FIV MODEL TO STUDY DRUG THERAPIES ON LENTIVIRUS-INDUCED CNS DISEASE

研究慢病毒引起的中枢神经系统疾病药物治疗的 FIV 模型

• 批准号: 6243146
• 负责人: Tom Ray Phillips
• 金额: $ 26.31万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-30 至 1998-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6243146
• 关键词: AIDS therapy; HIV infections; NMDA receptors; antiviral agents; cats; central nervous system disorders; combination chemotherapy; disease /disorder model; drug resistance; drug screening /evaluation; feline immunodeficiency virus; flow cytometry; genetic transcription; mutant; nervous system infection; neurotropic virus; nonhuman therapy evaluation; pharmacogenetics; psychoneuroimmunology; thalidomide; theobromine; tumor necrosis factor alpha; virus genetics; virus load; virus replication

There is a pressing need for appropriate animal models to screen promising new antivirals, assess the suitability of future chemotherapeutic targets, and compare different drugs and chemotherapeutic approaches in their ability to alter the course of lentivirus induced CNS disease. From the initial studies of this Center and the work of other investigators, the FIV/cat system has been developed into a legitimate model for the study of lentivirus pathogenesis of the CNS. Not only does FIV produce a disease that is very similar to human AIDS, but it is also similar to HIV at both the molecular and biochemical levels. In our Center, numerous parameters have been established to monitor the effects of virus infection on the CNS. We now want to expand these studies to investigate the effects of therapeutic agents on neurologic aspects of the disease. Additionally, we will examine the important therapeutic problem of virus resistance as well a mechanisms the virus uses to escape the effects of therapeutic agents. In this proposed project, we plan to specifically examine the effects of promising anti-TNF-alpha agents, the therapeutic outcome of NMDA receptor antagonists, the efficacy of new antiviral agents, and the effects of combined therapeutic agents on FIV induced neurological disease, as well as monitor for the development of drug-resistant mutants and map the genetic determinants associated with the resistant phenotype. Our long-term objective is to develop the FIV/cat system into a predictive animal model for assessing the effects of therapeutic compounds on the neurologic aspects of lentivirus diseases. It is important to examine not only how the therapeutic agent affects the neurologic form of the disease but also how the virus changes in response to the presence of the drug. In this set of proposed studies, we will examine new therapeutic approaches as well as the role antiviral resistant mutants play in lentivirus pathogenesis, enhancing our understanding of the interactions that occur among the lentivirus, host, and therapeutic agents. It is now time to use this system to gain insight into disease mechanisms as well as examine potential therapeutic approaches that ultimately may be used in human AIDS patients, as part of the Mitler/Darko Component of this Center.

目前迫切需要合适的动物模型来筛选有希望的 新的抗病毒药物，评估未来化疗靶点的适用性， 并比较不同的药物和化疗方法， 改变慢病毒诱导的CNS疾病的过程的能力。 从 该中心的初步研究和其他研究人员的工作， FIV/CAT系统已经发展成为一个合法的研究模型， CNS的慢病毒发病机制。 FIV不仅会导致疾病 这与人类艾滋病非常相似，但在两方面也与艾滋病毒相似 分子和生物化学水平。 在我们的中心， 已经建立了监测病毒感染对CNS的影响。 我们现在想扩大这些研究，以调查 治疗剂对疾病的神经方面的影响。 另外我们 也将研究病毒抗性的重要治疗问题 一种病毒用来逃避治疗药物作用的机制。 在这个拟议项目中，我们计划具体研究 有前途的抗TNF-α药物，NMDA受体的治疗结果 拮抗剂，新的抗病毒药物的疗效，以及 FIV诱导的神经系统疾病的联合治疗剂，以及 监测耐药突变体的发展，并绘制基因图谱， 与耐药表型相关的决定因素。 我们的长期 目的是将FIV/cat系统开发成预测性动物模型 用于评估治疗化合物对神经系统的影响 慢病毒病的一些方面。 重要的是不仅要研究如何 所述治疗剂影响疾病的神经学形式， 病毒对药物的反应是如何变化的 在这一套 我们将研究新的治疗方法， 抗病毒抗性突变体在慢病毒发病机制中的作用， 加强我们对发生在这些国家之间的相互作用的理解， 慢病毒、宿主和治疗剂。 现在是时候使用这个 系统，以深入了解疾病机制，以及检查潜在的 最终可能用于人类艾滋病患者的治疗方法， 作为该中心的Mitler/Darko组件的一部分。