Strategies Against HPV Related Genital Diseases in Women

人乳头瘤病毒（HPV）是女性下生殖道肿瘤的重要病因。与其他共致癌物和/或免疫缺陷的新相互作用导致肿瘤发生和癌症进展。然而，缺乏足够的动物模型和前瞻性临床试验阻碍了有效的抗hpv疗法的发展，并阻碍了对人类与这种病毒相互作用的彻底了解。该提案的目的是支持Bradley J. Monk医学博士的职业发展。在Luis P. Villarreal博士的指导下，Monk博士将在最近描述的严重联合免疫缺陷小鼠模型中使用植入的人HPV感染上皮和宫颈上皮内瘤变（CIN）来评估共同致癌物和抗病毒药物。Monk博士建议研究这些宫颈组织植入物的肿瘤转化以及进展或退行。将研究特定启动子或基因毒性化合物（如激素、尼古丁）以及新型抗hpv药物（如刺激免疫细胞、反义致癌基因）和营养补充剂（如吲哚- 3-甲醇或I3C）的影响。此外，在妇科肿瘤学家Philip J. DiSaia医学博士的指导下；Frank L. Meyskens，医学博士，具有化学预防专业知识的医学肿瘤学家；和Jeffrey S. Weber，医学博士，免疫学专业的肿瘤学家，Monk博士将进行两项新型HPV治疗的前瞻性临床试验。首先，在一项随机II期试验中，I3C是一种在十字花科蔬菜中发现并对HPV相关喉乳头状瘤病有效的化合物，将在HPV诱导的生殖器疣患者中进行评估。其次，计划在CIN女性中进行编码HPV 16型E7蛋白免疫原性部分的DNA质粒疫苗的I期和II期研究。Monk博士将专注于女性下生殖道肿瘤的抗hpv治疗领域的转化研究。在病毒学、化学预防、免疫学和妇科肿瘤学方面的导师将允许Monk博士在实验室和临床环境中研究独特的抗病毒药物，重点是HPV免疫。这条道路将使蒙克博士成为一名独立的研究者，能够首先在动物身上研究抗hpv疗法，然后在人类化学预防试验中进行研究。预计Monk博士将在申请支持期结束时获得实验室和临床研究的校外资金。

The human papillomavirus (HPV) is a significant etiologic agent in lower female genital tract neoplasia. Novel interactions with other co-carcinogens and/or immuno-deficiency lead to tumorigenesis and cancer progression. However, both the lack of adequate animal models and prospective clinical trials are impediments to the development of effective anti-HPV therapies and prevent a thorough understanding of human interactions with this virus. The objective of this proposal is to support the career development of Bradley J. Monk, M.D. Under the direction of Dr. Luis P. Villarreal, Ph.D., Dr. Monk will evaluate co-carcinogens and anti-viral agents in a recently described severe combined immunodeficiency mouse model using implanted human HPV infected epithelium, cervical intraepithelial neoplasia (CIN). Dr. Monk proposes to study the neoplastic transformation as well as the progression or regression of these cervical tissue implants. The influence of specific promoters or genotoxic compounds (e.g. hormones, nicotine) as well as novel anti-HPV agents (e.g. stimulated immune cells, anti-sense oncogenes) and nutritional supplements (e.g. indole 3-carbinol or I3C) will be studied. In addition, under the direction of Philip J. DiSaia, M.D., a Gynecologic Oncologist; Frank L. Meyskens, M.D., a Medical Oncologist with expertise in Chemoprevention; and Jeffrey S. Weber, M.D., Ph.D., a Medical Oncologist with expertise in Immunology, Dr. Monk will conduct two prospective clinical trials of novel HPV therapies. First, I3C, a compound found in cruciferous vegetables and effective in HPV related laryngeal papillomatosis, will be evaluated in patients with HPV induced genital warts in a randomized phase II trial. Second, a phase I and II study of a DNA plasmid vaccine encoding an immunogenic portion of the HPV type 16 E7 protein is planned among women with CIN. Dr. Monk will focus his career on translational research in the area of anti-HPVmodalities specifically related to female lower genital tract neoplasia. Mentors in Virology, Chemoprevention, Immunology and Gynecologic Oncology will allow Dr. Monk to investigate unique anti-viral agents both in the laboratory and in clinical settings with an emphasis on HPV immunity. This path will develop Dr. Monk into an independent investigator able to study anti-HPV therapies first in animals then in human chemoprevention trials. It is expected that Dr. Monk will have obtained extramural funding for both his laboratory and clinical studies by the end of the period of support requested.