Development of tissue explant models for microbicide evaluation

用于杀微生物剂评估的组织外植体模型的开发

• 批准号: 7174354
• 负责人: Thomas Hope
• 金额: $ 18.03万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7174354
• 关键词: HIV infections; clinical research; combination chemotherapy; communicable disease transmission; drug screening /evaluation; epithelium; female; human therapy evaluation; human tissue; local antiinfective agents; method development; penis; sex partner; tissue /cell culture; topical drug application; virus infection mechanism; virus replication

DESCRIPTION (provided by applicant): Unsuccessful attempts to develop a vaccine against HIV have led to a great need for new preventative strategies, the most encouraging of which are microbicides. An effective microbicide would decrease the severity of the AIDS epidemic by decreasing the rate of sexual transmission. A number of models systems have been developed to provide insights into the mechanisms of male-to-female sexual transmission including explant cultures and the rhesus macaque vaginal transmission model. These systems have been successfully used to evaluate and identify candidate microbicides. There has been much less progress in the development of systems to evaluate female-to-male sexual transmission. There are currently no model systems of female-to-male sexual transmission that can determine whether potential microbicides are capable of preventing infection via the penis. To fill this gap, this application seeks to develop an explant culture system using human penile tissue. This will enable the efficacy and safety of candidate microbicides that prevent the sexual transmission of HIV to males to be evaluated. Additionally, my laboratory has recently developed methodology that allows the detection of individual virions in tissue. This system will be further developed to determine how HIV normally interacts with human penile tissue. In the R21 component of this application we will optimize these systems to determine the normal interaction of HIV with intact tissue and subsequent viral replication. In the R33 phase of the application we will evaluate the potential of different candidate microbicides, individually and in combination, to alter HIV interaction with the tissue and prevent HIV infection and replication. We will also determine if exposure to the microbicide causes any changes in the tissue that may have deleterious effects on normal cell function. The application seeks to develop new methods that determine whether chemicals can be used to prevent the sexual transmission of HIV. These methods will be used to determine the potency of protection from HIV infection, and the safety of the compounds before they are tested in humans. It is hoped that preventing HIV infection will decrease the number of people in the world infected with HIV and slow the AIDS epidemic.

描述（由申请人提供）：针对艾滋病毒开发疫苗的尝试不成功，导致人们非常需要新的预防策略，其中最令人鼓舞的是生液剂。有效的菌心可以通过降低性传播率来降低艾滋病流行的严重程度。已经开发了许多模型系统，以提供有关男性到女性性传播机制（包括外植体培养物和恒河猴阴道传播模型）的机制的见解。这些系统已成功地用于评估和识别候选菌皮。在评估女性到男性性传播的系统发展方面的进展要少得多。目前尚无女性到男性性传播模型系统，可以确定潜在的微生物是否能够通过阴茎预防感染。为了填补这一空白，该应用程序旨在使用人类阴茎组织开发出epplant培养系统。这将使候选菌皮的功效和安全性能够防止艾滋病毒向男性的性传播。此外，我的实验室最近开发了允许在组织中检测单个病毒体的方法。该系统将进一步开发，以确定HIV通常如何与人类阴茎组织相互作用。在本应用的R21组件中，我们将优化这些系统，以确定HIV与完整组织的正常相互作用以及随后的病毒复制。在应用的R33阶段，我们将分别和组合不同候选菌皮的潜力来改变与组织的HIV相互作用，并防止HIV感染和复制。我们还将确定暴露于菌心是否会导致组织中可能对正常细胞功能产生有害影响的任何变化。 该应用程序旨在开发新方法，以确定是否可以使用化学物质来防止HIV的性传播。这些方法将用于确定艾滋病毒感染的保护效力，并在化合物在人类中进行测试之前的安全性。希望预防艾滋病毒感染能够减少世界上感染艾滋病毒并减缓艾滋病流行病的人数。