“Protection from MRSA lethality by inhibiting LXRα phosphorylation”

– 通过抑制 LXRα 磷酸化来防止 MRSA 致死 –

• 批准号: 10681027
• 负责人: Michael J. Garabedian
• 金额: $ 25.43万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-17 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10681027
• 关键词: Affect; Animals; Anti-Inflammatory Agents; Antibiotic Resistance; Antibiotic Therapy; Autophagocytosis; Binding; Biogenesis; Blood; Breeding; Cardiometabolic Disease; Cell model; Cell physiology; Cells; Cessation of life; Community-Acquired Infections; Cultured Cells; Dose; Endothelial Cells; Enterobacteria phage P1 Cre recombinase; Foundations; Gene Expression; Genes; Hospitals; Human; Impairment; Individual; Infection; Inflammatory; Inflammatory Response; Intervention; Intravenous; Knock-in Mouse; LXRalpha protein; Ligands; Macrophage; Measures; Mediating; Mus; Myeloid Cells; Natural Immunity; Pathogenesis; Pathology; Pathway interactions; Peripheral Blood Mononuclear Cell; Phosphorylation; Predisposition; Preventive; Publishing; Reporting; Resistance; Role; Serine; Serum; Staphylococcus aureus; Staphylococcus aureus infection; Streptococcus pneumoniae; Surface; Systemic infection; Testing; Therapeutic; Therapeutic Intervention; Tissues; Toxic effect; Toxin; United States National Institutes of Health; Variant; Virulence Factors; Wild Type Mouse; antimicrobial; cell type; chromatin immunoprecipitation; combat; comparison control; exosome; experimental study; gamma secretase; in vivo; inhibitor; intraperitoneal; methicillin resistant Staphylococcus aureus; monocyte; mortality; mouse model; neutrophil; novel strategies; pharmacologic; programs; promoter; receptor; response; small molecule; targeted treatment; therapeutic target; transcription factor; transcriptome; transcriptome sequencing; upstream kinase

PROJECT SUMMARY This proposal aims to determine whether LXRα phosphorylation at serine 196 (S196) is a possible target for therapeutic intervention in MRSA. Our previous published studies demonstrated in cultured cells and mouse models of cardiometabolic diseases that the non-phosphorylated form of LXRα S196A reprograms the LXR- modulated transcriptome and produces a more robust anti-inflammatory response. We hypothesize that reducing LXRα phosphorylation in myeloid and endothelial cells would reduce MRSA pathology via resistance to MRSA toxin-mediated killing via enhanced exosome release. To test this, we will develop a mouse model that harbors either myeloid or endothelial cell-specific LXRα S196A knock-in mice and compare the mortality and exosome abundance in the blood upon MRSA infection to that of WT LXRα mice and global LXRα S196A mice. We will also generate primary macrophages and endothelial cells from wild-type and LXRα S196A mice and measure effects on gene expression upon infection with MRSA to reveal genes and pathways modulated by LXRα S196 phosphorylation that can be manipulated for preventive and therapeutic purposes. We will also test whether pharmacological interventions that promote the non- phosphorylated form of the wild-type LXRα can protect wild-type mice and human PBMCs from lethal MRSA infection. Successful completion of the aims will determine whether LXRα phosphorylation represents a tractable target for treating MRSA due to its ability to reduce inflammatory gene expression.

项目概要 该提案旨在确定 LXRα 在丝氨酸 196 (S196) 处的磷酸化是否是一个可能的目标 我们之前发表的研究在培养细胞和小鼠中进行了证明。 心脏代谢疾病模型中，LXRα S196A 的非磷酸化形式重新编程 LXR- 调节转录组并产生更强大的抗炎反应。 骨髓细胞和内皮细胞中的 LXRα 磷酸化可通过对 MRSA 的耐药性来减少 MRSA 病理学 通过增强外泌体释放来毒素介导的杀伤。 为了测试这一点，我们将开发一种含有骨髓或内皮细胞特异性 LXRα S196A 的小鼠模型 敲入小鼠并比较 MRSA 感染与 WT 的死亡率和血液中的外泌体丰度 LXRα 小鼠和全局 LXRα S196A 小鼠我们还将产生原代巨噬细胞和内皮细胞。 野生型和 LXRα S196A 小鼠并测量感染 MRSA 后对基因表达的影响以揭示 由 LXRα S196 磷酸化调节的基因和途径，可用于预防和治疗 我们还将测试药物干预是否能促进非治疗目的。 野生型 LXRα 的磷酸化形式可以保护野生型小鼠和人类 PBMC 免受致命的 MRSA 侵害 成功完成目标将决定 LXRα 磷酸化是否代表一种易于处理的感染。 由于其能够减少炎症基因表达，因此成为治疗 MRSA 的靶点。