ROLES(S) OF GLYCOSPHINGOLIPIDS IN NEURAL AIDS

鞘糖脂在神经艾滋病中的作用

• 批准号: 6394466
• 负责人: Cara-Lynne Schengrund
• 金额: $ 23.17万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6394466
• 关键词: AIDS /HIV neuropathy; HIV envelope protein gp120; brain cell; embryo /fetus tissue /cell culture; glycosphingolipids; human fetus tissue; human immunodeficiency virus 1; virus infection mechanism

Description (Adapted from Applicant's abstract): Glycospingolipids (GSLs) have been implicated as fusion co-factors for human immunodeficiency virus (HIV) the causative agent of AIDS. The overall goal of the proposed research is to determine the role(s) of GSLs in the interaction of HIV-1-associated gp120 with different cell types of the central nervous system (CNS) or models thereof, and to use that information to develop possible inhibitors of that interaction. Emphasis is placed on CNS cells or possible models thereof because many individuals infected with HIV-1 eventually develop HIV-1-associated dementia (HAD) in the absence of opportunistic infection. The specific aims of this proposal are to: 1) identify which GSL(s) is/are the ligand(s) for HIV-1-associated gp120. Experiments will be done to confirm that GSLs are necessary for HIV-1 entry and, in those instances where they are necessary, the GSLs adhered to by HIV-1 will be identified. 2) determine the contribution of the GSL saccharide and ceramide moieties to interactions with HIV-1-associated gp120. Experiments will be carried out to determine whether the saccharide portion of each GSL adhered to by HIV-1 can inhibit HIV-1 adherence to the GSL immobilized on plastic or whether a "multivalent" saccharide or the ceramide portion per se is needed. 3) determine whether the inhibitor of HIV-1 associated gp120-mediated adherence to a GSL is able to inhibit gp120-mediated entry of the virus into cells expressing the GSL. The effectiveness of the inhibitor identified in the 2nd aim at blocking infection will be monitored using microglia and asrtrocytes. The effectiveness of the virus at inducing apoptosis in neuroblastoma cells in the presence and absence of inhibitor will also be ascertained. The results should indicate the portion of the GSL(s) recognized by HIV-1. They may also provide the basis for development of an inhibitor able to block adherence of HIV-1 to its GSL fusion co-factor thereby blocking its entry into the cell.

描述（改编自申请人的摘要）：糖鞘脂（GSL）具有 被认为是人类免疫缺陷病毒（HIV）的融合辅因子 艾滋病的病原体。拟议研究的总体目标是 确定 GSL 在 HIV-1 相关 gp120 与 中枢神经系统（CNS）或其模型的不同细胞类型，以及 使用该信息来开发该相互作用的可能抑制剂。 重点放在中枢神经系统细胞或其可能的模型上，因为许多 感染 HIV-1 的个体最终会发展为 HIV-1 相关痴呆症 (HAD) 在没有机会性感染的情况下。本次活动的具体目标 建议是： 1) 确定哪个 GSL 是配体 HIV-1 相关的 gp120。将进行实验以确认 GSL 是 HIV-1 进入所必需的，并且在必要的情况下， HIV-1 所遵循的 GSL 将被识别。 2）确定贡献 GSL 糖和神经酰胺部分与 HIV-1 相关的相互作用 GP120。将进行实验以确定糖是否 HIV-1 所粘附的每个 GSL 的一部分可以抑制 HIV-1 对 GSL 的粘附 固定在塑料上或者是“多价”糖还是神经酰胺 部分本身是需要的。 3) 确定是否为HIV-1抑制剂 相关的 gp120 介导的 GSL 粘附能够抑制 gp120 介导的 病毒进入表达 GSL 的细胞。的有效性 将监测第二次鉴定的旨在阻止感染的抑制剂 使用小胶质细胞和星形胶质细胞。病毒诱导的有效性 在存在或不存在抑制剂的情况下，神经母细胞瘤细胞的凋亡将 也得以确定。结果应表明 GSL 的部分 被HIV-1识别。它们还可以为开发提供基础 抑制剂能够阻断 HIV-1 与其 GSL 融合辅因子的粘附，从而 阻止其进入细胞。