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）：易受收购艾滋病毒风险的脆弱人群包括种族少数群体。尽管非裔美国人占美国人口的13％，但他们约占艾滋病毒/艾滋病的一半新诊断。自2000年以来，有几份报告表明，HAART患有艾滋病毒/艾滋病的人的口服HPV增长正在增加，而这在弱势群体中，例如非裔美国人，比白人更普遍。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口服并发症的敏感性。人类β防御素（HBD）已成为我们小组在艾滋病毒研究的重点已有七年多了。我们发现口服上皮细胞衍生的β防御素可以：1）艾滋病毒诱导； 2）抑制病毒感染免疫能力细胞的能力； 3）与特定的趋化因子和类似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/或高度活跃的抗逆转录病毒疗法（HAART）使口服粘膜易于细胞和先天免疫障碍。有趣的是，在先天免疫分子的曲目中，HBD是独一无二的，因为仅报道了Beta Defensin基因簇的拷贝数变化。可能解释了HBD表达水平的人际变异性。我们的多学科计划是通过将支持项目的教师和核心设施的直接合作和互动来协同的。项目1和项目2中的研究人员将在两个项目中合作设计，生产和共享变化的β防御蛋白分子的形式，这些分子将用于结构/功能研究，以探索与趋化因子和Toll样受体相互作用的防御素相互作用。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研究，以探讨上皮细胞和抗原呈递细胞之间的串扰。项目3和4将共享从口腔疣和与HIV相关的其他口服粘膜并发症中分离出的组织，以检查其蛋白质和基因组谱。因此，这些项目高度融合在理论和协作基础上，并涉及多学科方法，其中包括防御素生物学，结构化学，HIV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产生有关我们中心假设的总体结论。所有数据将通过PIS与外部咨询小组之间的会议进行严格的科学审查，该小组将通过行政核心组织（核心A）。

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