Oral Mucosal Immunity in Vulnerable HIV Infected Populations

易受艾滋病毒感染人群的口腔粘膜免疫

• 批准号: 8462465
• 负责人: AARON WEINBERG
• 金额: $ 173.68万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-15 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8462465
• 关键词: AIDS/HIV problem; Accounting; African American; Antigen-Presenting Cells; Aphthous Stomatitis; Biology; Biostatistics Core; CXCR4 gene; Cells; Chronic; Collaborations; Communicable Diseases; Complication; Copy Number Polymorphism; Core Facility; Cytomegalovirus; Data; Defense Mechanisms; Defensins; Dermatology; Diagnosis; Disease; Epithelial; Epithelial Cells; Faculty; Frequencies; Gene Cluster; Gene Dosage; Genes; Genetic; Genetic Predisposition to Disease; Genomics; Growth; HIV; HIV Infections; HIV Seropositivity; Health Services Accessibility; Highly Active Antiretroviral Therapy; Homeostasis; Host Defense; Human; Human Papillomavirus; Immune; Immune system; Immunocompetent; Immunology; Impairment; Incidence; Infection; Minority; Mucosal Immunity; Natural Immunity; Oral; Oral Manifestations; Oral candidiasis; Oral mucous membrane structure; Pathology; Patients; Periodontal Diseases; Play; Population; Populations at Risk; Predisposing Factor; Predisposition; Proteins; Proteomics; Regulation; Reporting; Research; Research Personnel; Role; Simplexvirus; Structural Chemistry; Structure; Sum; TLR1 gene; Tissues; Toll-like receptors; Universities; Variant; Virus; Vulnerable Populations; base; beta-Defensins; chemokine; design; information gathering; interdisciplinary approach; meetings; microbial; multidisciplinary; oral HPV; oral wart; programs; response

DESCRIPTION (provided by applicant): Vulnerable populations at risk of acquiring HIV include racial minorities. While African Americans make up13% of the US population, they account for about half of the HIV/AIDS new diagnoses. Since 2000, several reports have suggested that oral HPV growths are increasing in people with HIV/AIDS on HAART, and that this is more prevalent in vulnerable populations, such as African Americans than Whites. The central hypothesis of this Program Project is that alterations in innate defense mechanisms determine susceptibility to oral complications following HIV infection. Human beta defensins (hBDs) have been the focus of our group's research in HIV for more than seven years. We have discovered that oral epithelial cell-derived beta defensins can: 1) be induced by HIV; 2) inhibit the ability of the virus to infect immunocompetent cells; and 3) interact with specific chemokine and toll-like receptors resulting in regulation of adaptive immune cells. Moreover, chronic HIV infection and/or highly active antiretroviral therapy (HAART) predisposes the oral mucosae to both cellular and innate immune impairment. Interestingly, amongst the repertoire of innate immune molecules, hBDs are unique, as copy number variations have only been reported for the beta defensin gene cluster; possibly explaining the interpersonal variability in hBD expression levels. Our multidisciplinary program is synergistic through the direct collaboration and interaction of our faculty and core facilities that will support the projects. Investigators in Project 1 and Project 2 will cooperatively design, produce, and share altered forms of beta defensin molecules that will be utilized in structure/function studies in both projects that explore defensin interactions with chemokine and toll-like receptors. Investigators from Projects 1 and 3 will utilize expertise in immunology and dermatology to design and implement studies that explore the cross-talk between epithelial cells and antigen presenting cells. Projects 3 and 4 will share tissue isolated from oral warts and other oral mucosal complication associated with HIV to examine their protein and genomic profiles. Thus, these projects are highly integrated on both a theoretical and collaborative basis and involve a multidisciplinary approach that includes expertise in defensin biology, structural chemistry, HIV immunology, dermatology and genetics. Finally, projects will be supported by the Proteomics and Biostatistics Core (Core B), and information gathered through the Program Project will be examined so that the sum of the data may generate overarching conclusions regarding our central hypothesis. All the data will be subjected to rigorous scientific scrutiny through meetings between the PIs and an External Advisory Panel that will be organized through the Administrative Core (Core A).

描述（由申请人提供）：有感染艾滋病毒风险的弱势群体包括少数族裔。虽然非裔美国人占美国人口的 13%，但他们约占艾滋病新诊断病例的一半。自 2000 年以来，一些报告表明，接受高效抗逆转录病毒疗法 (HAART) 的艾滋病毒/艾滋病患者口腔 HPV 的增长正在增加，而且这种情况在非洲裔美国人等弱势群体中比白人更为普遍。该计划项目的中心假设是先天防御机制的改变决定了艾滋病毒感染后对口腔并发症的易感性。七年多来，人类β防御素（hBD）一直是我们小组艾滋病毒研究的重点。我们发现口腔上皮细胞衍生的β防御素可以：1）由HIV诱导； 2）抑制病毒感染免疫活性细胞的能力； 3) 与特定趋化因子和 Toll 样受体相互作用，从而调节适应性免疫细胞。此外，慢性HIV感染和/或高效抗逆转录病毒治疗（HAART）使口腔粘膜容易受到细胞和先天免疫损伤。有趣的是，在先天免疫分子的所有分子中，hBD 是独一无二的，因为仅报道了 β 防御素基因簇的拷贝数变异；可能解释 hBD 表达水平的人际差异。我们的多学科项目通过支持项目的教员和核心设施的直接合作和互动而发挥协同作用。项目 1 和项目 2 的研究人员将合作设计、生产和共享改变形式的 β 防御素分子，这些分子将用于两个项目的结构/功能研究，探索防御素与趋化因子和 Toll 样受体的相互作用。项目 1 和 3 的研究人员将利用免疫学和皮肤病学方面的专业知识来设计和实施探索上皮细胞和抗原呈递细胞之间相互作用的研究。项目 3 和 4 将共享从口腔疣和其他与 HIV 相关的口腔粘膜并发症中分离出来的组织，以检查其蛋白质和基因组谱。因此，这些项目在理论和协作基础上高度整合，涉及多学科方法，包括防御素生物学、结构化学、艾滋病毒免疫学、皮肤病学和遗传学方面的专业知识。最后，项目将得到蛋白质组学和生物统计学核心（核心 B）的支持，并且将检查通过计划项目收集的信息，以便数据的总和可以生成关于我们的中心假设的总体结论。所有数据都将通过 PI 和外部咨询小组之间的会议接受严格的科学审查，该会议将通过行政核心（核心 A）组织。

项目成果

Human papillomavirus oncogenic E6 protein regulates human β-defensin 3 (hBD3) expression via the tumor suppressor protein p53.

• DOI: 10.18632/oncotarget.8443
• 发表时间: 2016-05-10
• 期刊: Oncotarget
• 作者: DasGupta T;Nweze EI;Yue H;Wang L;Jin J;Ghosh SK;Kawsar HI;Zender C;Androphy EJ;Weinberg A;McCormick TS;Jin G
• 通讯作者: Jin G

Variation in human β-defensin genes: new insights from a multi-population study.

• DOI: 10.1111/iji.12021
• 发表时间: 2013-08
• 期刊: International journal of immunogenetics
• 影响因子: 2.2
• 作者: Mehlotra RK;Zimmerman PA;Weinberg A;Jurevic RJ
• 通讯作者: Jurevic RJ

Proteomic and bioinformatic profile of primary human oral epithelial cells.

原代人口腔上皮细胞的蛋白质组学和生物信息学特征。

• DOI: 10.1021/pr3007254
• 发表时间: 2012
• 期刊: Journal of proteome research
• 影响因子: 4.4
• 作者: Ghosh,SantoshK;Yohannes,Elizabeth;Bebek,Gurkan;Weinberg,Aaron;Jiang,Bin;Willard,Belinda;Chance,MarkR;Kinter,MichaelT;McCormick,ThomasS
• 通讯作者: McCormick,ThomasS