Role of Cellular Sialidase in Pathogenesis of HIV-1

描述(由申请人提供)：近期和长期职业目标：(I) 在大型医学中心进行临床相关研究；(Ii) 在传染病/内科病房照顾病人；及(Iii)训练 研究生、医学研究员和住院医生。 研究职业发展计划：我现在正处于我职业生涯的一个阶段 临床技能扎实，需要经过培训才能开展扎实的研究 程序。本培训期间的一个主要目标是获得 所需的科学和组织专业知识，以进行竞争性和 自主创新生物医学研究。我将通过以下方式实现这一目标 增加了我对糖生物学、病毒-细胞相互作用和新的 分子和细胞生物学技术，并通过培养一种 用来评估我的数据的统计分析。研究，学术 和人类病毒学与医学研究所的临床环境 马里兰大学中心将提供完美的机会 实现这些目标。 研究背景和目标：糖蛋白的生物活性 在自然界中的分布受到唾液酸调节的影响 内容。神经氨酸酶(在哺乳动物细胞中称为唾液酸酶)去除 糖偶联物的末端唾液酸基残基，从而影响蛋白质和 细胞功能。我们已经证明了糖共轭化合物的脱除 外周血单核细胞表面增强了HIV-1的感染性。这项提议的目的是 是：(一)澄清细胞死亡与细胞死亡之间的关系 糖蛋白与HIV-L感染外周血单核细胞的关系(1) 纯化的淋巴细胞和单核细胞的去分析促进感染和(2) 在糖苷的数量和类型之间有直接的关系 从细胞表面去除的唾液酸键和 提高传染性和(Ii)阐明其发病机制(S) 通过确定(1)是否促进HIV-1在所需的PBMC中的生长 细胞表面糖偶联物的缺失影响早期事件 病毒-细胞相互作用，(2)CD4和HIV-1的辅助受体是 活化的外周血单核细胞中的相对低脂解离和(3)细胞解离 表面糖结合物激活PBMC，诱导细胞因子的产生或 上调HIV-1的表面CD4和辅助受体的表达。

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.