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: 7295740
• 负责人: Thomas Hope
• 金额: $ 21万
• 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 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7295740
• 关键词: Acquired Immunodeficiency Syndrome; Biological Models; Cell physiology; Chemicals; Computer Systems Development; Detection; Development; Epidemic; Evaluation; Exposure to; Female; HIV; HIV Infections; Human; Individual; Infection prevention; Laboratories; Macaca mulatta; Methodology; Methods; Modeling; Normal Cell; Numbers; Phase; Rate; Safety; Severities; Sexual Transmission; System; Testing; Tissues; Vaccines; Viral; Virion; insight; male; microbicide; penis; prevent; vaginal transmission

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）：研制艾滋病毒疫苗的尝试失败，导致非常需要新的预防战略，其中最令人鼓舞的是杀微生物剂。一种有效的杀菌剂将通过降低性传播率来降低艾滋病流行的严重程度。许多模型系统已经被开发出来，以提供对雄性到雌性性传播机制的见解，包括外植体培养和恒河猴阴道传播模型。这些系统已成功地用于评价和鉴定候选杀微生物剂。在发展评估女性对男性性传播的系统方面，进展要小得多。目前还没有女性对男性性传播的模型系统，可以确定潜在的杀菌剂是否能够防止通过阴茎感染。为了填补这一空白，本应用程序寻求利用人类阴茎组织开发外植体培养系统。这将使预防艾滋病毒向男性性传播的候选杀微生物剂的有效性和安全性得到评估。此外，我的实验室最近开发了一种方法，可以检测组织中的单个病毒粒子。该系统将进一步发展，以确定HIV通常如何与人类阴茎组织相互作用。在本应用程序的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和随后的病毒复制。在申请的R33阶段，我们将评估不同候选杀菌剂的潜力，单独或联合，改变HIV与组织的相互作用，防止HIV感染和复制。我们还将确定接触杀微生物剂是否会导致组织发生任何可能对正常细胞功能产生有害影响的变化。