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HIV infection of male genital tissue (R21)

男性生殖组织的 HIV 感染（R21）

基本信息

批准号：
6944285
负责人：
ROBIN J SHATTOCK
金额：
$ 10.8万
依托单位：
U OF L ST. GEORGE'S HOSPITAL MEDICAL SCH
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-09-01 至 2006-08-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Sexual transmission of HIV-1, the major mode of HIV-1 infection world-wide, occurs across mucosal surfaces. In the face of an expanding epidemic there is an urgent need for effective strategies to block mucosal spread of this infection. However, success of any preventative strategy may be critically dependent upon detailed knowledge of the mechanisms of transmission. While much has been learnt about vaginal and/or rectal transmission, relatively little is known about the mechanisms of HIV transmission to male genital tissue. Indeed, factors governing such transmission and the events between exposure of male genital mucosal surfaces and establishment of clinical infection are still poorly understood. The number and frequency of target cells, the relative susceptibility of different tissue sites (foreskin, glans and urethra) and the mechanisms of trans-epithelial transmission have not been investigated in a systematic fashion. This project aims to test the hypothesis that tissue specific determinants govern relative susceptibility to HIV-1 infection and replication in male genital tissue. In particular, the relative frequency of potential target cells, and receptor expression, will be correlated to ex vivo susceptibility of male genital tissue explants (foreskin, glans and urethra) to HIV-1 infection (cell free and cell associated, using a range of isolates). Male genital tissue will be obtained, with consent, from gender reassignment and other surgical procedures, and optimal culture conditions will be determined using techniques developed for other mucosal explant models (cervical/rectal) already established in the applicant's laboratory. To determine potential mechanisms for any differential susceptibility to HIV infection, the principal target cells for infection, and/or uptake of virus by migratory cells within the different tissue sites will be defined. The use of specific receptor/co-receptors in such mechanisms will be confirmed using a range of available antagonists and blocking Mabs. These studies may provide a major contribution to our understanding of the determinants of HIV-1 infection of male genital tissue, which in turn could be key to successful targeting of strategies and topical microbicides designed to block the sexual spread of HIV infection. The proposed "R21 grant" builds on the applicant's proven track record in investigation of HIV replication in cervical and rectal tissue models, and will bring added value to a number of NIH funded microbicide related programme project grants already underway in the applicant's laboratory.

描述(申请人提供)：HIV-1的性传播是世界范围内HIV-1感染的主要方式，发生在粘膜表面。面对不断扩大的疫情，迫切需要采取有效的战略来阻止这种感染的粘膜传播。然而，任何预防性策略的成功可能关键取决于对传播机制的详细了解。虽然关于阴道和/或直肠传播的知识很多，但对艾滋病毒传播到男性生殖器组织的机制知之甚少。事实上，控制这种传播的因素以及男性生殖器粘膜表面暴露与临床感染之间的事件仍然知之甚少。靶细胞的数量和频率、不同组织部位(包皮、龟头和尿道)的相对易感性以及跨上皮传播的机制尚未得到系统的研究。该项目旨在测试组织特异性决定因素控制男性生殖器组织对HIV-1感染和复制的相对易感性的假设。特别是，潜在靶细胞的相对频率和受体的表达将与男性生殖器组织外植体(包皮、龟头和尿道)对HIV-1感染(使用一系列分离株的无细胞和细胞相关)的体外易感性相关。在征得同意的情况下，男性生殖器组织将从变性和其他外科手术中获得，并将使用为申请人实验室已建立的其他粘膜外植体模型(宫颈/直肠)开发的技术来确定最佳培养条件。为了确定对艾滋病毒感染的任何不同易感性的潜在机制，将定义感染的主要靶细胞，和/或不同组织部位内的迁移细胞摄取病毒。将使用一系列可用的拮抗剂和阻断单抗来证实在这种机制中使用特定的受体/辅受体。这些研究可能为我们理解男性生殖器组织感染HIV-1的决定因素做出重大贡献，这反过来可能是成功地针对旨在阻止艾滋病毒感染的性传播的策略和局部杀微生物剂的关键。拟议的“R21资助”建立在申请者在宫颈和直肠组织模型中研究艾滋病毒复制的可靠记录的基础上，并将为申请者实验室中已在进行的一些由NIH资助的与杀微生物剂相关的项目资助带来附加值。