The Intersection between Cell-Intrinsic Innate Immunity and Metabolic Sensing

细胞固有的先天免疫与代谢传感之间的交叉点

• 批准号: 9556722
• 负责人: Alex Compton
• 金额: $ 47.94万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 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/9556722
• 关键词: Address; Antiviral Agents; Benefits and Risks; CCR; Catabolic Process; Cell Line; Cells; Cellular Metabolic Process; Clinical; Crystallization; Epithelial Cells; FRAP1 gene; Gene-Modified; Goals; HIV; Human; Immune response; Immunosuppressive Agents; Infection; Lead; Link; Mediating; Metabolic; Natural Immunity; Nature; Pathway interactions; Patients; Pharmaceutical Preparations; Predisposition; Proteins; Regimen; Reporting; Route; Sirolimus; Tissues; Vesicular stomatitis Indiana virus; Virus; Virus Diseases; Work; base; cell growth; cellular targeting; gene therapy; improved; inhibitor/antagonist; mTOR inhibition; permissiveness; therapeutic gene; vacuolar H+-ATPase

All work in my section began in February 2017, so there are no CCR-based accomplishments to report yet. Nonetheless, the goals and objectives of the project have crystallized. Our preliminary work using rapamycin on transformed epithelial cell lines has revealed that mTOR inhibition confers a 4- to 20-fold enhancement of infection, depending on the nature of the virus challenge and, specifically, the route of virus entry into cells. Furthermore, we found that the rapamycin-dependent enhancement of infection is reversed by inhibitors of endosomal acidification (v-ATPase), revealing that the enhancement requires active degradation of cellular factors via the lysosomal pathway. We are currently determining whether the effect on cellular susceptibility is directly linked to macroautophagy, a catabolic process controlled by mTOR. Moreover, we plan to inhibit the PI3K-Akt-mTOR pathway upstream and downstream of mTOR to narrow down the cellular proteins directly implicated in the control of virus infection in these settings.

我所在部门的所有工作均于 2017 年 2 月开始，因此尚未报告基于 CCR 的成就。尽管如此，该项目的目的和目标已经明确。我们使用雷帕霉素对转化的上皮细胞系进行的初步研究表明，mTOR 抑制可使感染增强 4 至 20 倍，具体取决于病毒攻击的性质，特别是病毒进入细胞的途径。此外，我们发现雷帕霉素依赖性感染增强可被内体酸化抑制剂（v-ATP酶）逆转，表明这种增强需要通过溶酶体途径主动降解细胞因子。我们目前正在确定对细胞敏感性的影响是否与巨自噬（一种由 mTOR 控制的分解代谢过程）直接相关。此外，我们计划抑制 mTOR 上游和下游的 PI3K-Akt-mTOR 通路，以缩小与这些环境中病毒感染控制直接相关的细胞蛋白范围。