The oral mucosal proteome: perturbation in HIV infection and Candida co infection

口腔粘膜蛋白质组：HIV 感染和念珠菌合并感染的扰动

• 批准号: 7603097
• 负责人: STEPHEN J CHALLACOMBE
• 金额: $ 25.64万
• 依托单位: KING'S COLLEGE LONDON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-17 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7603097
• 关键词: AIDS/HIV problem; Adherence; Affect; Binding; Biochemical; Biological Assay; Biological Phenomena; CCR5 gene; CD209 gene; CXCR4 gene; Candida; Candida albicans; Cells; Data; Dendritic Cells; Epithelial; Epithelial Cells; Epithelium; Etiology; Flow Cytometry; Frequencies; Gene Proteins; Genome; HIV; HIV Infections; HIV Receptors; Human; Immune; Immune response; Immunocompromised Host; Immunoelectron Microscopy; Infection; Investigation; Lasers; Lead; Leukocytes; Liquid substance; Macaca; Mannose; Mediating; Membrane; Modeling; Molecular Profiling; Mouth Diseases; Mucous Membrane; Natural Resistance; Nature; Opportunistic Infections; Oral; Oral Manifestations; Oral candidiasis; Oral cavity; Oral mucous membrane structure; Pathogenesis; Pathway interactions; Patients; Pattern; Physiological; Predisposition; Prevention; Prevention strategy; Process; Property; Protein Secretion; Proteins; Proteome; Proteomics; Quality of life; Research Personnel; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Role; Saliva; Salivary; Sampling; Science; Signal Pathway; Site; Surface; T-Lymphocyte; TLR4 gene; Technology; Time; Tissue Sample; Tissues; Toll-like receptors; Transcript; Transcription Factor AP-1; Vagina; Virus; antimicrobial; base; chemokine; cytokine; effective therapy; functional genomics; health care quality; in vivo; insight; multidisciplinary; novel; oral HIV; oral cavity epithelium; oral infection; oral tissue; pathogen; patient oriented research; programs; protective effect; receptor; receptor expression; reconstitution; response; therapy development; transmission process

DESCRIPTION (provided by applicant): This multidisciplinary application supports a strategy of combining patient-oriented research with the science based investigation of disease causation. The overall aim is to understand the mechanisms that apparently protect the oral epithelium from HIV infection. The long-term objective is to understand the basis of copathogenicity in the immunocompromised host leading to the delivery of more effective therapies. We hypothesize that HIV directly affects the oral epithelial proteome, leading to alterations that promote colonization and infection of the co-pathogen Candida. The specific aims are: 1) To fully characterize the constituents of the oral epithelium that protects the oral mucosa from HIV and Candida infection. Using oral and vaginal epithelial models, and human and macaque samples, the canonical receptors for both HIV and Candida will be investigated by flow cytometry. The epithelial proteome in the presence or absence of HIV and Candida will be then be fully characterized in order to identify protective or susceptibility factors to HIV and Candida infection in these mucosae. Saliva will be applied to the models to investigate the contribution of innate secretory factors present in oral fluids that may inhibit HIV or Candida infection Transcript profiling, quantitative RT-PCR, and Luminex protein assays will be performed to support the proteomic data. 2) To characterize the innate TLR-associated proteomic response elicited by human epithelium during HIV and Candida infection. The HIV- and C. a/b/cans-induced epithelial cytokine, chemokine, TLR1-10 and signaling pathway expression profiles will first be characterized in oral and vaginal epithelial models using proteomics. The PMN-dependent TLR-mediated protection mechanism against oral C. albicans infection will then be fully characterized using transcript profiling, real-time RT-PCR, confocal and immunoelectron microscopy, and siRNAi. Relevance: HIV/AIDS is most commonly transmitted through mucosal membranes. In some circumstances, the oral tissues are exposed to HIV but rarely become infected. Understanding the mechanism by which the oral cavity is apparently protected from infection could lead to the development of therapies to protect other mucosal tissues such as the vagina from infection and transmission of the virus. This could also lead to therapies for the treatment of the co-infections associated with HIV such as oral Thrush.

描述（由申请人提供）：这种多学科应用支持将面向患者的研究与基于科学的疾病因果关系结合的策略。总体目的是了解显然保护口腔上皮免受HIV感染的机制。长期目标是了解免疫功能低下的宿主中共同致病性的基础，从而导致提供更有效的疗法。我们假设艾滋病毒直接影响口服上皮蛋白质组，从而改变促进共生念珠菌的定殖和感染的改变。具体目的是：1）充分表征保护口腔粘膜免受HIV和念珠菌感染的口服上皮的成分。使用口服和阴道上皮模型以及人和猕猴样品，将通过流式细胞仪研究HIV和念珠菌的规范受体。然后，将对在存在或不存在HIV和念珠菌的情况下的上皮蛋白质组进行充分表征，以鉴定这些粘膜中的HIV和念珠菌感染的保护性或易感性因素。唾液将应用于模型，以研究可能抑制HIV或念珠菌感染的转录物分析，定量RT-PCR和Luminex蛋白测定的口服流体中存在的先天分泌因子的贡献，以支持蛋白质组学数据。 2）表征人类上皮在HIV和念珠菌感染期间引起的与先天TLR相关的蛋白质组学反应。 HIV-和C。A/B/CANS诱导的上皮细胞因子，趋化因子，TLR1-10和信号传导途径表达曲线将首先在口服和阴道上皮模型中使用蛋白质组学进行表征。然后，使用转录物分析，实时RT-PCR，共焦和免疫电子显微镜和siRNAI，将对白色念珠菌感染的PMN依赖性TLR介导的保护机制进行全面表征。相关性：艾滋病毒/艾滋病通常是通过粘膜膜传播的。在某些情况下，口腔组织暴露于HIV，但很少受到感染。了解口腔明显保护不受感染的机制可能导致疗法的发展，以保护其他粘膜组织，例如阴道，免受病毒的感染和传播。这也可能导致治疗与艾滋病毒相关的共同感染（例如口服鹅口疮）的疗法。