Candida albicans Epithelial Cell Interactions and Oropharyngeal Disease

白色念珠菌上皮细胞相互作用与口咽疾病

• 批准号: 8469749
• 负责人: Scott G Filler
• 金额: $ 33.47万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8469749
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Antifungal Agents; Azole resistance; Azoles; Binding; Candida albicans; Cell Communication; Cell Surface Proteins; Cell Wall; Cell surface; Characteristics; Chitinase; Complex; Data; Defect; Development; Diabetes Mellitus; Disease; E-Cadherin; Endocytosis; Epithelial Cells; Foundations; Funding; Gene Targeting; Genes; Goals; Grant; HIV; Head and Neck Cancer; Hexose Transporter; Highly Active Antiretroviral Therapy; Host Defense Mechanism; Immune; Immunocompromised Host; Immunosuppression; In Vitro; Incidence; Individual; Invaded; Mediating; Microarray Analysis; Morbidity - disease rate; Mus; Neutropenia; Opportunistic Infections; Oral; Organism; Oropharyngeal; Pathogenesis; Pathogenicity; Patients; Phosphotransferases; Play; Population Heterogeneity; Public Health; Receptor Cell; Receptor Protein-Tyrosine Kinases; Research; Role; Signal Transduction Pathway; Sjogren' s Syndrome; Specific qualifier value; Steroids; Therapeutic; Virulence; Work; base; cell injury; complement 1q receptor; human PHEMX protein; insight; meetings; mouse model; mutant; new therapeutic target; novel strategies; novel therapeutics; oropharyngeal thrush; overexpression; pathogen; patient population; prevent; public health relevance; receptor binding

DESCRIPTION (provided by applicant): Candida albicans is an opportunistic pathogen that causes oropharyngeal disease in a large and diverse population of patients, including those with HIV/AIDS, Sjogren's syndrome, diabetes mellitus, and cancer of the head and neck. Azole antifungal agents are the current mainstay of therapy for oropharyngeal candidiasis. However, because of the emergence of azole resistance, it is critical to develop novel strategies to prevent and treat this disease. Our goal is to identify new C. albicans virulence genes and to determine the mechanisms by which they contribute to pathogenicity. This information holds promise to identify new therapeutic targets for antifungal strategies. C. albicans invades oral epithelial cells by inducing its own endocytosis. In the previous project period, we discovered that C. albicans Als3 is an invasin that binds to E-cadherin on the epithelial cell surface and induces the endocytosis of the organism. Recently, we have determined that there are additional epithelial cell surface proteins that mediate endocytosis. These epithelial cell surface proteins include the globular C1q receptor (gC1qR) and the Met receptor tyrosine kinase. Also, the tetraspanin, CD151 likely organizes E-cadherin, gC1qR, and Met into a functional complex. We have also discovered that the C. albicans kinase, Tpk2 governs the capacity of C. albicans to invade and damage oral epithelial cells in vitro, as well as cause oropharyngeal candidiasis in mice. Further, Tpk2 governs the expression of the C. albicans chitinase, Cht2 and hexose transporter, Hgt12, which play key roles in C. albicans interaction with epithelial cells. In this project, we will 1) determine the functional interactions among E-cadherin, gC1qR, Met, and CD151 in epithelial cell invasion and damage by C. albicans; 2) determine the mechanisms by which C. albicans Cht2 and Hgt12 govern epithelial cell invasion, damage, and virulence; and 3) use overexpression-rescue and null mutant analysis to identify additional target genes of Tpk2 that mediate epithelial cell invasion and damage.

描述（由申请方提供）：白色念珠菌是一种机会致病菌，可导致大量不同人群的口咽疾病，包括HIV/AIDS、干燥综合征、糖尿病和头颈癌患者。唑类抗真菌药物是目前治疗口咽念珠菌病的主要药物。然而，由于唑类耐药性的出现，开发新的策略来预防和治疗这种疾病至关重要。我们的目标是确定新的C。白念珠菌毒力基因，并确定其致病机制。这一信息有望确定新的抗真菌策略的治疗靶点。 C.白色念珠菌通过诱导其自身的内吞作用侵入口腔上皮细胞。在上一个项目期间，我们发现C。白色念珠菌Als 3是一种侵袭素，其结合上皮细胞表面上的E-钙粘蛋白并诱导生物体的内吞作用。最近，我们已经确定，有额外的上皮细胞表面蛋白介导的内吞作用。这些上皮细胞表面蛋白包括球状C1 q受体（gC 1 qR）和Met受体酪氨酸激酶。此外，四跨膜蛋白CD 151可能将E-钙粘蛋白、gC 1 qR和Met组织成功能复合物。我们还发现C.白念珠菌激酶Tpk 2控制着白念珠菌的能力。白念珠菌在体外侵袭和破坏口腔上皮细胞，以及在小鼠中引起口咽念珠菌病。此外，Tpk 2控制C.白念珠菌几丁质酶Cht 2和己糖转运蛋白Hgt 12在白念珠菌中起关键作用。白色念珠菌与上皮细胞的相互作用。本研究的目的是：1）探讨E-钙粘蛋白、gC 1 qR、Met和CD 151在大肠杆菌侵袭和损伤上皮细胞中的相互作用; 2）确定C.白色念珠菌Cht 2和Hgt 12控制上皮细胞侵袭、损伤和毒力;和3）使用过表达拯救和无效突变分析来鉴定介导上皮细胞侵袭和损伤的Tpk 2的另外的靶基因。