Nanomaterials for engineering protection in the genital mucosa

用于生殖粘膜工程保护的纳米材料

基本信息

批准号：
8355391
负责人：
Kim A. Woodrow
金额：
$ 231.75万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-30 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8355391
关键词：
AIDS prevention AIDS/HIV problem Animal Model Antibodies Antigen-Presenting Cells Antigens Award Biocompatible Materials Biomedical Engineering Chronology Engineering Equilibrium Female Funding Mechanisms Genital system HIV HIV Infections HIV vaccine HIV-1 Health Priorities Immune response Immunity Immunization Immunology Infection Knowledge Measures Molecular Mucosal Immunity Mucous Membrane Nanotechnology Outcomes Research Pathogenesis Pharmaceutical Preparations Prevention Prevention Research Prevention strategy Preventive Process Recruitment Activity Research Research Proposals Site Testing Time Vaccination Vaccines Vagina Virus abstracting adaptive immunity base design global health high reward high risk immune activation innovation microbicide mucosal vaccine nanocarrier nanomaterials nanoparticle novel strategies pathogen prevent public health relevance response transmission process uptake vaccination strategy

项目摘要

DESCRIPTION (Provided by the applicant) Abstract: There is currently no clinically approved biomedical prevention strategy to prevent sexual HIV-1 transmission, which is the leading cause of new HIV infections worldwide. Although suboptimal alone, microbicide and vaccine strategies implemented together could fundamentally alter HIV prevention by providing protection during the immunization period, reducing infectious challenge, or boosting virus-specific mucosal immunity. Vaccine strategies that recruit and activate antigen-presenting cells, particularly DCs, at the site of immunization while at the same time inhibiting their capacity to enhance HIV-1 transmission may tip the balance towards boosting immunity rather than promoting infection. We have developed a nanoparticle microbicide and mucosal vaccine combination to generate a niche in the vaginal mucosa where mucosal DCs are recruited for immune activation but are protected from HIV-1 infection. We hypothesize that immunizing microbicide nanoparticles will recruit and activate DCs at the site of vaccination where HIV-1 infection and transmission are rendered non-permissive. In this New Innovator Award, I plan to engineer DC chemo- attracting nanocarriers that elute ARV drugs, demonstrate that enhanced DC uptake and processing of immunogens delivered from these nanocarries correlates with increased immunological responses, and test the nanocarriers in a relevant animal model to measure the quality and magnitude of the antigen-specific mucosal antibody and cellular immune responses that are elicited. This research proposal is particularly well suited for this unique funding mechanism because it proposes innovative, high-risk, and high-reward research at the interface of bioengineering and immunology that would have a major impact on HIV/AIDS research and prevention. The proposal is highly innovative because it integrates nanotechnology with HIV-1 pathogenesis and prevention immunology to design novel strategies based on newly emerging but unexplored concepts in chemo-vaccination to protect mucosal tissue from pathogen invasion. The approach is risky because evidence suggests that the lower female genital tract is a poor inductive site for adaptive immunity. The successful outcome of this research has the potential to fundamentally alter how microbicides and vaccines are used for HIV prevention, create a mechanism for effective immunization in the lower female genital tract, and provide a strategy for vaccination at other mucosal tissue. Public Health Relevance: Developing a safe and effective preventive HIV vaccine is a global health priority. This research proposal integrates knowledge about the chronology and molecular basis of sexual HIV transmission and infection with strategies for biomaterials engineering to deliver chemo-vaccines that will confer protective mucosal immunity.

描述（由申请人提供）摘要：目前尚无临床批准的生物医学预防策略来预防 HIV-1 性传播，这是全球新发 HIV 感染的主要原因。尽管单独使用杀菌剂和疫苗策略效果不佳，但同时实施杀微生物剂和疫苗策略可以通过在免疫期间提供保护、减少感染挑战或增强病毒特异性粘膜免疫，从根本上改变艾滋病毒预防。在免疫部位招募并激活抗原呈递细胞（尤其是 DC），同时抑制其增强 HIV-1 传播能力的疫苗策略可能会倾向于增强免疫力而不是促进感染。我们开发了一种纳米颗粒杀微生物剂和粘膜疫苗组合，以在阴道粘膜中产生一个生态位，粘膜 DC 被招募用于免疫激活，但免受 HIV-1 感染。我们假设，免疫杀微生物剂纳米颗粒将在不允许 HIV-1 感染和传播的疫苗接种部位招募并激活 DC。在这个新创新者奖中，我计划设计能够洗脱抗逆转录病毒药物的 DC 化学吸引纳米载体，证明增强的 DC 摄取和处理从这些纳米载体传递的免疫原与增强的免疫反应相关，并在相关动物模型中测试纳米载体以测量抗原特异性粘膜抗体和引起的细胞免疫反应的质量和强度。该研究提案特别适合这种独特的资助机制，因为它提出了生物工程和免疫学交叉领域的创新、高风险和高回报的研究，这将对艾滋病毒/艾滋病的研究和预防产生重大影响。该提案具有高度创新性，因为它将纳米技术与 HIV-1 发病机制和预防免疫学相结合，根据化疗疫苗中新出现但未经探索的概念设计新策略，以保护粘膜组织免受病原体侵袭。这种方法是有风险的，因为有证据表明女性下生殖道是一个不良的诱导部位。适应性免疫。这项研究的成功结果有可能从根本上改变杀菌剂和疫苗用于艾滋病毒预防的方式，创建女性下生殖道有效免疫的机制，并提供一种疫苗接种策略其他粘膜组织。公共卫生相关性：开发安全有效的预防性艾滋病毒疫苗是全球健康的优先事项。该研究计划将有关艾滋病毒性传播和感染的时间顺序和分子基础的知识与生物材料工程策略相结合，以提供具有保护性粘膜免疫的化学疫苗。