Oncogenic Human Papillomavirus Protein Network

描述（由申请人提供）：本申请涵盖挑战领域06使能技术和特定挑战主题06-CA- 117。为基础研究提供新工具和见解的技术，具有更高的速度，成本效益，灵敏度，选择性或创造研究特定机制的新途径的能力，可以更好地了解癌症的发展和进展。感兴趣的是用于分子、亚细胞、细胞和细胞外结构/功能研究的技术;生物分子、分子复合物、亚细胞复合物、细胞和复杂混合物的捕获、分离和表征;以及促进开发更准确的体外和体内癌症模型（特别是人类癌症的小鼠模型）的技术。特别感兴趣的是新技术，增强对肿瘤微环境，癌症干细胞，复杂途径和病原体在癌症发展中的作用的理解。人乳头瘤病毒（HPV）与多种人类癌症相关。目前已鉴定出100多种不同的HPV，其中约25种与人类癌症有关。乳头瘤病毒可以基于序列相关性被分组到系统发育树中。与癌症相关的HPV分为两个不同的组，α乳头瘤病毒属和β乳头瘤病毒属。α属的HPV主要感染生殖道和上呼吸道的粘膜上皮，β属的HPV引起皮肤损伤。这些属中的每一个中的HPV通过序列相关性进一步分组为在某种程度上预测生物学行为和癌症风险的物种。在α-HPV中，与宫颈癌相关的高危型（包括HPV 16、HPV 18、HPV 31、HPV 33、HPV 45和HPV 52）见于种属7和9。低风险的HPV，如与性病疣相关的HPV 6和HPV 44，在种属10中。HPV 2和HPV 57与任何癌症无关，不会引起生殖器粘膜病变，属于种属4。现在，分子和流行病学研究已经充分确定了α-HPV的7和9种成员在癌症中的作用。大约90%的人宫颈癌携带高危HPV类型的DNA，并表达两种作为病毒致癌基因的基因（E6和E7）。我们对α HPV属促进癌症进展的机制的大部分理解来自于对与HPV编码蛋白结合并相互作用的细胞蛋白的鉴定。β属的HPV引起皮肤病变。这些HPV中的许多首先在患有罕见皮肤病疣状表皮发育不良（EV）的患者的皮肤病变和癌症中被发现。这些HPV类型也在免疫抑制和免疫活性个体的鳞状细胞皮肤癌（SCSC）中发现，并且在正常个体的皮肤拭子和眉毛样本中发现。β HPV类型在人类SCSC中的机制作用尚不清楚。其中一些HPV（如HPV 5和HPV 8）与SCSC的相关性比其他HPV更强。这可能是因为，像α病毒属一样，某些β病毒属可能比其他病毒属具有更高的癌症进展风险。从分子的角度来看，β病毒属尚未得到很好的研究，它们可能导致癌症进展的机制仍有待阐明。这项挑战补助金提案结合了哈珀和豪利实验室的专业知识，以提供新的HPV工具，并应用CompPASS，一种新的计算和信息平台，用于蛋白质复合物和相互作用网络的蛋白质组学分析，为致癌HPV的生物学及其导致人类癌症的机制提供新的见解。 公共卫生相关性：人乳头瘤病毒是与许多人类癌症相关的病毒家族。与这些病毒相关的细胞发病机制以及它们如何导致癌症的重要见解来自HPV病毒编码蛋白靶向的细胞蛋白的鉴定。我们将为18种不同的HPV类型编码的病毒蛋白生成一套研究工具，这些HPV类型代表与癌症相关的两种不同的HPV属，并将确定与它们相互作用的细胞蛋白和途径。

DESCRIPTION (provided by applicant): This application broad Challenge Area 06 Enabling Technologies and specific Challenge Topic 06-CA- 117. Technologies that provide new tools and insights for basic research with increased speed, cost efficiency, sensitivity, selectivity, or the capability to create new avenues of research into the specific mechanisms that can lead to a better understanding of the development and progression of cancer. Of interest are technologies for molecular, subcellular, cellular and extracellular structure/function studies; capture, separation, and characterization of biomolecules, molecular complexes, sub-cellular complexes, cells, and complex mixtures; and technologies to facilitate the development of more accurate in vitro and in vivo cancer models (especially mouse models for human cancers). Of specific interest are new technologies that enhance understanding of the tumor microenvironment, cancer stem cells, complex pathways, and the role of pathogens in cancer development. The human papillomaviruses (HPVs) are associated with a variety of human cancers. Over 100 different HPVs have now been identified and about 25 of these have been associated with human cancer. The papillomaviruses can be grouped into a phylogenetic tree based on sequence relatedness. The cancer associated HPVs fall into two different groups, the genus alpha papillomaviruses and the genus beta papillomaviruses. The HPVs of genus alpha primarily infect mucosal epithelium of the genital tract and the upper airway, and the HPVs of the genus beta cause cutaneous lesions. The HPVs in each of these genera are further grouped by sequence relatedness into species that are somewhat predictive of biological behavior and cancer risk. Among the alpha-HPVs, the high-risk types (including HPV16, HPV18, HPV31, HPV33, HPV45 and HPV52) that are associated with cervical cancer are found in species 7 and 9. The low-risk HPVs, such as HPV6 and HPV44 associated with venereal warts, are in species 10. HPV2 and HPV57 are not associated with any cancers and do not cause genital mucosal lesions and are in species 4. The role of the species 7 and 9 members of the alpha-HPVs in cancer has now well been established by both molecular and epidemiologic studies. Approximately 90% of human cervical cancers harbor the DNA of a high-risk HPV type, and express two genes (E6 and E7) that function as viral oncogenes. Much of our understanding of the mechanisms by which the genus alpha HPVs contribute to cancer progression comes from the identification of the cellular proteins that bind and interact with HPV encoded proteins. The HPVs of the beta-genus cause cutaneous lesions. Many of these HPVs were first identified in skin lesions and cancers in patients with the rare dermatologic disease epidermodysplasia verruciformis (EV). These HPV types have also been found in squamous cell skin cancers (SCSC) from both immunosuppressed and immunocompetent individuals, and they have been found in skin swabs and eyebrow samples from normal individuals. The mechanistic role of the genus beta HPV types in human SCSC is less clear. The association of some of these HPVs (such as HPV5 and HPV8) with SCSC is stronger than for others. It may be that, like the genus alpha viruses, some of the genus beta viruses may present a higher risk for cancer progression than others. From a molecular standpoint, the genus beta viruses have not yet been well studied and the mechanisms by which they may contribute to cancer progression remain to be elucidated. This Challenge Grant proposal combines expertise from the Harper and Howley laboratories to provide new HPV tools, and to apply CompPASS, a new computational and informatic platform for proteomic analysis of protein complexes and interaction networks, to provide new insights into the biology of the oncogenic HPVs and the mechanisms by which they cause human cancer. PUBLIC HEALTH RELEVANCE: The human papillomaviruses are a family of viruses that are associated with a number of human cancers. Important insights into the cellular pathogenesis associated with these viruses and how they cause cancer have come from the identification of the cellular proteins that are targeted by HPV virally encoded proteins. We will generate a set of research tools for the viral proteins encoded by 18 different HPV types representing two distinct genera of HPVs that have been associated with cancer and will determine the cellular proteins and pathways with which they interact.