Novel Si RNA microbicides to prevent HIV-1 infectio

新型 Si RNA 杀菌剂预防 HIV-1 感染

• 批准号: 7132114
• 负责人: Bharat Ramratnam
• 金额: $ 18.18万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7132114
• 关键词: AIDS education /prevention; Macaca mulatta; RNA interference; antiviral agents; biotechnology; chemokine receptor; communicable disease control; cooperative study; gene induction /repression; human immunodeficiency virus 1; liposomes; mucosa; nanotechnology; nonhuman therapy evaluation; rectum /anus; sexually transmitted diseases; simian immunodeficiency virus; small interfering RNA; technology /technique development; topical drug application; vagina

Heterosexual transmission accounts for the majority of new cases of HIV-1 infection each year. Recent reports from the World Health Organization estimate that a total of 38 million people are now infected with HIV-1 worldwide; 90% of whom live in developing countries. Nearly 50% of all infected individuals were women. The increased incidence of HIV-1 infection in women, particularly those of childbearing age, underscores the urgent need for effective preventative and therapeutic options that are safe, affordable and culturally accepted. In the absence of an effective preventative vaccine, topical microbicides may offer a practical alternative to block HIV-1 transmission at the site of entry. We seek funds to determine whether the process of RNA interference (RNAi) can be harnessed to prevent the cervico-vaginal transmission of HIV-1 and thereby emerge as a novel microbicidal strategy. This work will be conducted by investigators at Rhode Island Hospital, Brown University (B. Ramratnam) and Harvard-NEPRC (K. Mansfield). RNAi refers to the sequence-specific degradation of RNA that follows the cellular introduction of homologous, short interfering (si) RNA. We hypothesize that RNAi can be specifically targeted to the mucosal surfaces and decrease the expression of host factors that mediate HIV-1/SIV mucosal transmission. For these proof-of-principle studies, we will target the CCR5 chemokine receptor in macaques. We will pursue three specific aims over the 12- month period. 1: To characterize the tissue penetrance of liposomal and nanaocapsule formulated siRNA following direct mucosal application. 2: To quantify the kinetics and durability of mucosal CCR5 knockdown following single and serial mucosal applications of siRNA. 3. To conduct virus challenge experiments in siRNA treated animals. At the end of the granting period, we will have defined the HIV-1 microbicidal potential of siRNA.

异性性传播占每年艾滋病毒-1感染新病例的大多数。最近 世界卫生组织的报告估计，目前共有3800万人感染了 HIV-1感染者遍布全球，其中90%生活在发展中国家。近50%的感染者是 妇女妇女，特别是育龄妇女感染艾滋病毒-1的发病率增加， 强调迫切需要安全、负担得起、 文化上接受。在缺乏有效的预防性疫苗的情况下，局部杀微生物剂可以提供 在入境地点阻断HIV-1传播的切实可行的替代办法。我们寻求资金，以确定 RNA干扰（RNAi）可以用来预防HIV-1的宫颈-阴道传播 从而成为一种新型的杀菌策略。这项工作将由罗德的调查人员进行 岛医院，布朗大学（B。Ramratnam）和Harvard-NEPRC（K.曼斯菲尔德）。RNAi是指 RNA的序列特异性降解，随后细胞引入同源的短干扰RNA， (si)核糖核酸我们假设RNAi可以特异性地靶向粘膜表面，并减少细胞内的细胞凋亡。 介导HIV-1/SIV粘膜传播的宿主因子的表达。对于这些原理验证研究， 我们将靶向猕猴体内的CCR 5趋化因子受体。我们将在12年内实现三个具体目标- 月期间。1：表征脂质体和纳米胶囊配制的siRNA的组织转染率 在直接粘膜应用之后。2：量化粘膜CCR 5敲低的动力学和持久性 在siRNA的单次和连续粘膜应用后。3.进行病毒挑战实验， siRNA处理的动物。在授权期结束时，我们将确定HIV-1杀菌剂 siRNA的潜力