Proj. 4-The Genetic Variation of Innate Immune Genes w/Oral Manifestations of HIV

项目。

基本信息

批准号：
8254425
负责人：
RICHARD J JUREVIC
金额：
$ 32.12万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8254425
关键词：
11p AIDS/HIV problem Acquired Immunodeficiency Syndrome Africa African American Agonist Aphthous Stomatitis Area Autoimmune Diseases Bacteria CD4 Positive T Lymphocytes CXCR4 gene Candidiasis Cause of Death Cells Cessation of life Chemotaxis Child Communicable Diseases Complex Complication Cytomegalovirus DEFB1 gene Defensins Development Disease Disease Progression Disease susceptibility Economic Factors Effectiveness Environment Epidemic Epithelial Epithelial Cells Ethnic Origin Family Family member Frequencies Gene Cluster Gene Dosage Gene Family Genes Genetic Genetic Polymorphism Genetic Predisposition to Disease Genetic Variation HIV HIV Infections HIV Seropositivity Hairy Leukoplakia Haplotypes Highly Active Antiretroviral Therapy Host Defense Human Human Papillomavirus Immune Immune System Diseases Immune response Immune system Immunosuppression Incidence Individual Infection Inflammation Mediators Inflammatory Kaposi Sarcoma Maintenance Mediating Microbe Mothers Mucosal Immunity Natural Immunity Opportunistic Infections Oral Oral Manifestations Oral candidiasis Oral cavity Oral mucous membrane structure Outcome Pathology Patients Peptides Periodontitis Play Population Predisposition Process Property Race Risk Role Signal Transduction Simplexvirus Single Nucleotide Polymorphism Stomatitis Structure Surface TLR1 gene Tissues Toll-like receptors Up-Regulation Variant Vertical Disease Transmission Viral Virus antimicrobial beta-Defensins fungus member microbial oral infection oral lesion oral wart outcome forecast receptor response socioeconomics treatment response

项目摘要

Oral manifestations of HIV have been documented since the initial presentation of the HIV/AIDS epidemic of the 80's. The most common oral complication was candidiasis, and was associated with a reduction in CD4+T cells. Oral candidal infection was a hallmark indicator of immune dysfunction. The increased incidence of opportunistic infections was related to immune suppression as evidenced by a reduction in number and functional activity of CD4 + T cells. The frequency and type of oral complication has changed since the initial description of the 80s. With the initiation of HAART therapies the constellation of oral manifestations has changed. The incidence of HPV associated warts and severe aphthous ulcer stomatitis has increased, whereas oral candidal infection and oral hairy leukoplakia has declined. In addition, not all patients develop these pathologies. The variation in disease presentation and concomitant response to therapy may be related to genetic predisposition of innate immune genes and variation in epithelial barrier function. Innate immunity is increasingly being recognized as playing a critical role in host defense against infectious diseases, including HIV. The defensin peptides have antimicrobial properties and are major protective components of the epithelial mucosal barrier. Genetic variation of the defensin genes in the form of SNPs and CNVs has been shown to be associated with disease susceptibility. Toll-like receptors (TLRs), a family of evolutionary conserved receptors on host cells including human oral epithelial cells, recognize specific microbial structures, leading to the up-regulation of inflammatory mediators and recruitment of inflammatory cells. Multiple interactions of microbes and host tissues and secreted antimicrobial molecules such as beta-defensins are involved in the maintenance of the homeostatic environment of the healthy mouth, however, little is known about the role of TLRs in this process or the impact of HIV disease on these processes. Polymorphisms in the TLR family and the common adaptor Tirap/Mal have been associated with many human infectious and autoimmune diseases. We hypothesize that host variation in TLRs and their signaling components contribute to the variability in oral infections seen in HIV disease by altering host/microbe interactions at the mucosal surface. We will decipher the relationship of genetic variations in both the defensin gene cluster and toll-like receptors TLR1 and 2 with oral manifestations of HIV/AIDS. We will define and correlate specific complex haplotypes with the frequency and occurrence of oral lesions in the HIV population. We hypothesize that susceptibility, prognosis, and outcome of HIV are associated with genetic variations in the defensin gene cluster. This same variation also may be associated with the development of oral complications following HIV infection

自从首次出现艾滋病毒/艾滋病流行以来，艾滋病毒的口腔表现就已被记录在案。 80年代。最常见的口腔并发症是念珠菌病，与口腔细菌感染减少有关。 CD4+T细胞。口腔念珠菌感染是免疫功能障碍的标志性指标。增加的机会性感染的发生率与免疫抑制有关，这一点可以通过减少 CD4 + T 细胞的数量和功能活性。口腔并发症的频率和类型发生了变化自 80 年代最初描述以来。随着 HAART 疗法的启动，一系列口服药物表现形式发生了变化。 HPV相关疣和严重口疮性溃疡性口腔炎的发生率增加，而口腔念珠菌感染和口腔毛状白斑减少。此外，并非所有患者出现这些病症。疾病表现和伴随反应的变化治疗可能与先天免疫基因的遗传倾向和上皮屏障的变化有关功能。人们越来越认识到先天免疫在宿主防御病毒方面发挥着关键作用。传染病，包括艾滋病毒。防御素肽具有抗菌特性，是主要的防御素肽。上皮粘膜屏障的保护成分。防御素基因的遗传变异形式 SNP 和 CNV 的数量已被证明与疾病易感性相关。 Toll 样受体 (TLR)、包括人类口腔上皮细胞在内的宿主细胞上进化保守的受体家族，识别特定的微生物结构，导致炎症介质的上调和招募炎症细胞。微生物和宿主组织以及分泌的抗菌分子的多重相互作用例如β-防御素参与维持健康的体内平衡环境然而，人们对 TLR 在此过程中的作用或 HIV 疾病对这些过程的影响知之甚少。流程。 TLR 家族和通用接头 Tirap/Mal 中的多态性与许多人类传染病和自身免疫性疾病。我们假设 TLR 的宿主变异及其信号成分通过改变艾滋病毒疾病中口腔感染的变异性粘膜表面的宿主/微生物相互作用。我们将破译遗传变异的关系防御素基因簇和 Toll 样受体 TLR1 和 2 均与 HIV/AIDS 的口腔表现有关。我们将定义特定的复杂单倍型并将其与口腔病变的频率和发生率相关联艾滋病毒人群。我们假设 HIV 的易感性、预后和结果与防御素基因簇的遗传变异。同样的变化也可能与 HIV 感染后口腔并发症的发展