Role of Cellular Sialidase in Pathogenesis of HIV-1

细胞唾液酸酶在 HIV-1 发病机制中的作用

• 批准号: 6450482
• 负责人: NICHOLAS MILTON STAMATOS
• 金额: $ 11.94万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6450482
• 关键词: CD4 molecule; N acylation; clinical research; cytokine receptors; enzyme activity; exo alpha sialidase; glycoproteins; host organism interaction; human immunodeficiency virus 1; human subject; lymphocyte; monocyte; tissue /cell culture; virus infection mechanism; CD4 molecule; N acylation; clinical research; cytokine receptors; enzyme activity; exo alpha sialidase; glycoproteins; host organism interaction; human immunodeficiency virus 1; human subject; lymphocyte; monocyte; tissue /cell culture; virus infection mechanism

DESCRIPTION (provided by applicant): Immediate and long-term career goals: (i) To conduct clinically-relevant research at a major medical center, (ii) To care for patients on an Infectious Diseases/Medicine ward and (iii) To train graduate students and medical fellows and residents. Research career development plan: I am now at a point in my career where my clinical skills are solid and need the training to develop a solid research program. A major objective during this training period is to acquire the scientific and organizational expertise needed to conduct competitive and innovative biomedical research independently. I will achieve this goal by increasing my knowledge of glycobiology, virus-cell interactions and new techniques of molecular and cellular biology and by developing an appreciation of statistical analyses with which to evaluate my data. The research, academic and clinical environments of the Institute of Human Virology and the Medical Center of the University of Maryland will provide the perfect opportunities to meet these goals. Research - Background and Aims: The biological activity of glycoproteins distributed throughout nature is influenced by modulation of their sialic acid content. Neuraminidase (referred to as sialidase in mammalian cells) removes terminal sialyl residues from glycoconjugates, and thus influences protein and cell function. We have demonstrated that desialylation of glycoconjugates on the surface of PBMCs enhances infectivity of HIV-1. The aims of this proposal are (I) to clarify the relationship between desialylation of cellular glycoproteins and infection of PBMCs by HIV-l by determining whether (1) desialylation of purified lymphocytes and monocytes promotes infection and (2) there is a direct correlation between the amount and type of glycosidic linkage of sialic acid removed from the cell surface and the degree of enhancement in infectivity and (II) to elucidate the mechanism(s) for the enhanced growth of HIV -1 in desialylated PBMCs by determining whether (1) desialylation of cellular surface glycoconjugates influences early events in the virus-cell interaction, (2) CD4 and the co-receptors for HIV-1 are relatively hyposialylated in activated PBMCs and (3) desialylation of cellular surface glycoconjugates activates PBMCs, induces production of cytokines or upregulates the surface expression of CD4 and co-receptors for HIV-1.

描述（由申请人提供）：立即和长期职业目标：（i） 在主要医疗中心（II）进行临床与临床相关的研究 照顾感染性疾病/医学病房和（iii）训练患者 研究生和医疗研究员和居民。 研究职业发展计划：我现在正处于职业生涯中 临床技能是扎实的，需要培训来开发扎实的研究 程序。在此培训期间的一个主要目标是获取 开展竞争性和组织专业知识 独立的创新生物医学研究。我将通过 提高我对糖脂学，病毒 - 细胞相互作用和新的知识 分子和细胞生物学的技术，并通过发展欣赏 用于评估我的数据的统计分析。研究，学术 人类病毒学研究所和医学研究所的临床环境 马里兰大学中心将为 实现这些目标。 研究 - 背景和目的：糖蛋白的生物活性 分布在整个自然界受到其唾液酸的调节影响 内容。神经氨酸酶（哺乳动物细胞中称为唾液酸酶）去除 糖缀合物的末端siAlyl残基，从而影响蛋白质和 细胞功能。我们已经证明了在 PBMC的表面增强了HIV-1的感染性。该提议的目的 是（i）阐明细胞脱酰化之间的关系 HIV-L通过确定（1）是否通过HIV-L对PBMC的糖蛋白和PBMC感染 纯化的淋巴细胞和单核细胞的脱酰化促进感染，（2） 糖苷的数量和类型之间存在直接相关性 从细胞表面去除的唾液酸的连锁和程度 增强感染性和（ii）以阐明机制的机制 通过确定（1）是否是否确定脱酰化PBMC中HIV -1的生长增强 细胞表面糖缀合的脱酰化影响早期事件 病毒细胞相互作用，（2）CD4和HIV-1的共受体是 在活化的PBMC中相对脱糖化，（3）细胞脱酰化 表面糖缀合物激活PBMC，诱导细胞因子的产生或 上调HIV-1的CD4和共受体的表面表达。