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Mouse modeling of HPV infection

HPV感染的小鼠模型

基本信息

批准号：
10054175
负责人：
Chien-Fu Hung
金额：
$ 59.54万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10054175
关键词：
3-Dimensional Adherent Culture Animal Model Animals Anogenital cancer Anogenital venereal warts Antibodies Antigen Targeting Antigens Antiviral Therapy Anus C57BL/6 Mouse CD4 Positive T Lymphocytes Canis familiaris Capsid Carcinoma in Situ Cattle Cell Culture Techniques Cell Line Cervical Clinic Clinical Cutaneous DNA DNA Vaccines Data Development Disease Electroporation Epidermodysplasia Verruciformis Epithelial Etiology Exhibits Gardasil Genetic Goals HIV HPV-High Risk Head and Neck Cancer High grade dysplasia House mice Human Papilloma Virus Vaccine Human Papilloma Virus-Related Malignant Neoplasm Human Papillomavirus Human Pathology Human papilloma virus infection Human papillomavirus 16 Human papillomavirus 18 Human papillomavirus 6 Human papillomavirus HPV L1 protein Immune Immunity Immunocompetent Immunologics Immunosuppressive Agents Inbred Mouse India Infection Inherited Intervention Knock-out Laboratory mice Life Cycle Stages Malignant Neoplasms Malignant Squamous Cell Neoplasm Malignant neoplasm of cervix uteri Modeling Mucous Membrane Mus Nude Mice Oral cavity Organ Transplantation Oryctolagus cuniculus Papilloma Papillomavirus Patients Phase Population Preventive vaccine Prophylactic treatment Public Health Reagent Reporter Research Personnel Risk Site Skin Carcinoma Skin Papilloma Squamous cell carcinoma System Tail Testing Therapeutic Therapeutic Studies Translational Research Transplant Recipients UV Radiation Exposure Ultraviolet Rays Vaccinated Vaccination Vaccines Vagina Viral Virion Virus Virus Diseases Virus-like particle base carcinogenesis carcinogenicity clinically relevant cohort comparative efficacy cost efficacy evaluation follow-up high risk human model immune resistance immunogenicity mouse model neonate neoplastic cell novel novel therapeutics novel vaccines prevent protective efficacy screening success therapeutic candidate tool tumor tumorigenesis vaccine response vaccine trial

项目摘要

SUMMARY Our overall goal is to create a laboratory mouse-based model of human papillomavirus (HPV) infection and disease to support the development of novel HPV vaccines. Translational research requires animal models that are robust representations of human pathology in which to test questions of clinical importance, and provide reliable information for the development of novel interventions and patient benefit. HPV is the primary etiologic agent of at least 5% of all cancers worldwide, mostly cervical and subsets of other anogential and head and neck cancers and potentially also non-melanoma skin cancers. Unfortunately, there is no specific antiviral therapy, but vaccine-based approaches are very promising. Many groups are bringing candidate therapeutic HPV vaccines to the clinic, including our pNGLV4aCRTE6E7L2 DNA, but to date there has been limited success in treating patients despite promising data with the vaccines in the current standard animal models. This demonstrates the need for more predictive animal models. HPV does not complete its life cycle and produce virions in mice or in cell culture monolayers and so HPV pseudovirions delivering a reporter construct are often used. This system does not fully mimic the assembly and maturation of the viral capsid in E4-expressing differentiating epithelium or provide a disease endpoint. A model that produces disease from virus produced in a papilloma and expressing clinically-relevant HPV sequences is required. Therefore, we propose to transform the utility of Mus musculus papillomavirus type 1 (MmuPV1) by incorporating key HPV sequences and credential it for use as a model for testing novel therapeutic and protective HPV vaccines. SPECIFIC AIM 1: To develop MmuPV1 viruses incorporating HPV sequences. Organ transplant recipients (OTRs) and HIV+ patients exhibit more severe and progressive HPV disease, and dramatically higher rates of HPV-associated malignancies. Non-melanoma skin cancers (NMSC) in immune-compromised patients are associated with a plethora of βHPVs that were initially described in epidermodysplasia verruciformis (EDV) patients. SPECIFIC AIM 2: To develop an MmuPV1-based mouse challenge model of human cohorts at normal and high risk for the development of HPV-associated cancer. To validate these new murine models of HPV infection and disease we propose to examine the efficacy of a licensed HPV vaccine and two of our clinical grade experimental vaccines that will shortly enter early phase testing: RG1-VLP, a single virus-like particle antigen intended to provide broad immunity against diverse HPV types, and the candidate therapeutic DNA vaccine pNGLV4aCRTE6E7L2 administered via electroporation. SPECIFIC AIM 3: To compare the efficacy of the Gardasil 9, pNGLV4aCRTE6E7L2 DNA and RG1-VLP vaccines against disease and viral endpoints in murine models of healthy subjects and those at high risk for HPV-related cancer.

摘要我们的总体目标是创建一种以小鼠为基础的人类乳头瘤病毒(HPV)感染模型，并以支持新型HPV疫苗的开发。翻译研究需要动物模型它们是人类病理学的有力代表，在其中测试具有临床重要性的问题，以及为新干预措施的开发和患者的利益提供可靠的信息。人乳头瘤病毒是主要的全世界至少5%的癌症的病因，主要是宫颈癌和其他类似和头颈部癌症和潜在的非黑色素瘤皮肤癌。不幸的是，没有具体的抗病毒治疗，但基于疫苗的方法非常有希望。许多团体都带来了候选人治疗性HPV疫苗应用于临床，包括我们的pNGLV4aCRTE6E7L2 DNA，但到目前为止已经有治疗患者的成功有限，尽管目前标准动物的疫苗数据很有希望模特们。这表明需要更具预测性的动物模型。HPV没有完成其生命周期并在小鼠或细胞培养单层中产生病毒粒子，因此HPV假病毒粒子正在传递记者构造是经常使用的。该系统不能完全模拟病毒衣壳的组装和成熟。 E4-表达分化上皮或提供疾病终点。制造疾病的模型在乳头状瘤中产生并表达与临床相关的HPV序列的病毒是必需的。因此，我们建议通过整合关键的HPV来改变小鼠乳头瘤病毒1型(MmuPV1)的效用测序和认证，作为测试新型治疗性和保护性HPV疫苗的模型。特异性目的1：建立整合HPV序列的MmuPV1病毒。器官移植受者 (OTRs)和HIV+患者表现出更严重和更进行性的HPV疾病，并显著增加人乳头瘤病毒相关的恶性肿瘤。免疫受损患者中的非黑色素瘤皮肤癌(NMSC) 与最初在疣状表皮发育不良中描述的过多的βHPV有关病人。特定目的2：建立基于MmuPV1的人类队列小鼠挑战模型 HPV相关癌症的正常和高危发展。为了验证这些新的小鼠 HPV感染和疾病的模型我们建议检查一种有执照的HPV疫苗和两种我们即将进入早期测试的临床级实验疫苗：Rg1-VLP，一种类似单一病毒的疫苗旨在对各种HPV类型提供广泛免疫力的颗粒抗原，以及候选的治疗方法 DNA疫苗pNGLV4aCRTE6E7L2通过电穿孔接种。具体目标3：比较 Gardasil 9、pNGLV4aCRTE6E7L2 DNA疫苗和RG1-VLP疫苗对疾病和病毒的免疫效果在健康受试者和HPV相关癌症高危人群的小鼠模型中的终点。