人乳头瘤病毒 16 型和 18 型感染的细胞表面事件-猫眼课题宝

人乳头瘤病毒 16 型和 18 型感染的细胞表面事件

批准号：

8500124

负责人：

Martin Sapp

金额：

$33.74万

依托单位：

LOUISIANA STATE UNIV HSC SHREVEPORT

依托单位国家：

美国

项目类别：

财政年份：

2009

资助国家：

美国

项目状态：

已结题

起止时间：

2009-07-17 至 2016-06-30

来源：

https://reporter.nih.gov/project-details/8500124

关键词：

Accounting Address Affect Amino Acids Antibodies Binding Binding Sites Biochemical Biological Biological Assay Biology Capsid Capsid Proteins Cell Culture Techniques Cell surface Cell-Matrix Junction Cells Cervix carcinoma Clathrin Cleaved cell Collaborations Complement Confocal Microscopy Crystallization Cyclophilins DNA Viruses Data Development Endocytosis Endosomes Epidermis Event Extracellular Matrix Family Generations Genetic Transcription Genome Goals Heparan Sulfate Proteoglycan Heparin Heparin Binding Human Papilloma Virus-Related Malignant Neoplasm Human Papillomavirus Human papilloma virus infection Human papillomavirus 16 Human papillomavirus 18 In Vitro Incidence Infection Intracellular Transport Investigation Knock-out L1 viral capsid protein L2 viral capsid protein Lesion Life Cycle Stages Los Angeles Lysine Malignant - descriptor Malignant Neoplasms Maps Mediating Medical Microtubules Minor Molecular Molecular Conformation Monoclonal Antibodies Mutagenesis N-terminal Nuclear Peptidylprolyl Isomerase Pharmaceutical Preparations Pharmacotherapy Population Process Proteins Research Roentgen Rays Role Screening for cancer Secretory Vesicles Site Small Interfering RNA Staging Structure Testing Viral Viral Genome Virion Virus Wit Woman cellular targeting cyclophilin B ds-DNA fighting human PHEMX protein inhibitor/antagonist knock-down mutant neutralizing monoclonal antibodies particle prevent programs public health relevance receptor small molecule tool transcription factor PML uptake

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DESCRIPTION (provided by applicant): Human papillomaviruses (HPV) form a large family of viruses some of which are associated with various forms of cancer, including cervical carcinoma. They induce more than seven per cent of all cancers in women worldwide. Especially, HPV pose a burden to women in underdeveloped regions in the world due to a lack of access to cancer screening programs. The long term goal of this research is to understand early events of HPV infection with the focus on events occurring on the cell surface. The major capsid protein, L1, of HPV type 16 is primarily responsible for initial binding of virus to heparan sulfate proteoglycan (HSPG) present on cell surface and extracellular matrix (ECM). Attachment to HSPG induces a shift in the conformation of L1 and the minor capsid protein, L2, both of which we can now detect with monoclonal antibodies. X-ray structure analysis in collaboration with X. Chen identified several HSPG binding sites on the viral capsid. Our preliminary data suggest their sequential use in primary attachment and secondary binding events as well for inducing conformational shifts. In addition, we collected evidence for an involvement of Cyclophilin B (CyPB) in two distinct steps during HPV infection: mediating L2 conformational changes on the cell surface and facilitating uncoating of the viral genome. Aim 1 will test our hypothesis that two HS binding sites on the viral capsid are sequentially used during cell surface events of HPV infection. This will be achieved by a structure-guided mutagenesis of HS binding sites. Aim 2 is intended to delineate the function of Cyclophilins in HPV infection using siRNA knock down and small molecule inhibitors combined with biochemical and cell biological approaches. Aim 3 is dedicated to understand the processes underlying the conformational shifts affecting both capsid proteins in molecular detail. Understanding these events in detail will allow the development of interfering strategies to fight HPV-induced malignant lesions.

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