Development of novel quantitative methods for in vivo assessment of mucosal irrit

开发用于体内粘膜刺激评估的新型定量方法

基本信息

批准号：
9251644
负责人：
Massoud Motamedi
金额：
$ 59.42万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-03-01 至 2020-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9251644
关键词：
AIDS prevention Address Advanced Development Animal Model Architecture Biological Assay Biological Markers Cells Chronic Clinical Trials Colposcopy Detection Development Diagnostic Procedure Dose Endoscopy Environment Epithelial Evaluation Failure Formulation Gel Goals HIV HIV Infections Human Image Imaging Techniques Immune response Immunology procedure Incidence Infection Inflammation Inflammatory Injury Longitudinal Studies Mediator of activation protein Methodology Methods Microanatomy Microscopy Modeling Monitor Morphology Mucous Membrane Optical Coherence Tomography Outcome Permeability Play Predisposition Prevention Prevention strategy Preventive Public Health Resolution Role Safety Savings Sheep Techniques Technology Tenofovir Testing Tissues Topical agent Topical application Translating Vagina Validation Virion base biomarker evaluation biomarker panel combat imaging approach improved in vivo in vivo Model irritation microbicide microendoscopy molecular imaging nanoparticle next generation novel novel strategies preclinical safety prevent product development public health relevance quantitative imaging rectal response safety testing tool vaginal microbicide

项目摘要

DESCRIPTION (provided by applicant): The goal of this project is to develop sensitive and quantitative imaging and cellular approaches for the evaluation of vaginal and rectal mucosal responses to non-vaccine biomedical prevention (nBP) products aimed at preventing acquisition of HIV. A safe and effective nBP strategy could contribute to reducing the incidence of HIV saving millions of lives. While several promising candidate nBPs have emerged in recent years and progressed to clinical trials, a disappointing outcome has been the halting of several such trials due to safety concerns or failure to prevent HIV. These outcomes highlight the need for improved preclinical safety assessment of candidate nBPs, including the need for the sensitive diagnostic methods that can assess the degree of nBP-induced damage in the mucosal barrier and that can detect the presence of inflammatory cells and mediators that may contribute to increased susceptibility to infection. However, there is a critical gap in the availability of advanced tools for monitoring the in vivo mucosal microenvironment in the context of nBP products, particularly in readily accessible animal models that provide a mucosal environment similar to humans in gross and micro-anatomy and scale. Supporting models and technologies that provide an avenue for non-invasive and repeated in vivo assessment of mucosal barrier response to nBP prevention strategies could play an important role in the nBP pipeline, significantly contributing to the development of more safe and effective products. Here, we hypothesize that changes in microstructure and permeability of mucosal barrier can be detected by subcellular and molecular imaging of vaginal and rectal mucosa in vivo, following topical application of nBPs. Our specific aims are to develop and validate novel cellular and molecular imaging techniques for quantitative monitoring and detection of mucosal irritation with sensitivity that is not currently available, and to validate these techniques as a marker of mucosal irritation and injury that can be correlated to inflammation following topical applications of nBP. The expected outcomes include the development of more sensitive epithelial barrier assessment approaches than are currently available for evaluating the effects of nBPs and advancing the use of the sheep model for in vivo assessment of candidate nBPs, thereby contributing to the pipeline for development of safe and effective nBPs.

描述（由申请人提供）：该项目的目的是开发敏感和定量的成像和细胞方法，以评估对旨在防止获得HIV获取的非疫苗生物预防（NBP）产品的阴道和直肠粘膜反应。安全有效的NBP策略可能有助于减少艾滋病毒挽救数百万生命的发生率。尽管近年来已经出现了几个有前途的NBP，并发展到临床试验，但由于安全问题或未能预防HIV而导致的几项此类试验导致了令人失望的结果。这些结果凸显了需要改善候选NBP的临床前安全评估，包括需要评估NBP诱导的粘膜屏障损伤程度的敏感诊断方法，并可以检测炎症细胞和介体的存在，从而有助于增加感染感染的易感性。但是，在NBP产品的背景下，高级工具的可用性有一个危险的差距，尤其是在易于使用的动物模型的情况下，这些动物模型提供了类似于人类的粘膜环境，该模型与人类类似于人类的粘膜和微型分析和尺度。支持模型和技术为NBP管道中对NBP预防策略的粘膜屏障响应的无创和重复评估提供途径，这在NBP管道中起着重要作用，从而有助于开发更安全有效的产品。在这里，我们假设可以通过局部应用NBP的阴道和直肠粘膜的亚细胞和直肠粘膜的亚细胞和分子成像来检测粘膜屏障的变化和粘膜屏障的渗透性。我们的具体目的是开发和验证新型的细胞和分子成像技术，以定量监测和检测粘膜刺激并敏感目前尚不可用，并验证这些技术是粘膜刺激的标记 NBP局部应用后可能与炎症有关的损伤。预期的结果包括开发更敏感的上皮屏障评估方法，目前可用于评估NBP的影响以及推进使用绵羊模型来体内评估候选NBP的影响，从而有助于开发安全和有效NBP的管道。