“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.

项目摘要 该提案旨在确定丝氨酸196（S196）的LXRα光术是否是可能的目标 MRSA的治疗干预。我们先前发表的研究在培养细胞和小鼠中证明 心脏代谢疾病的模型，即LXRαS196A的非磷酸化形式重编程LXR- 调制转录组并产生更强大的抗炎反应。我们假设减少了 LXRα的髓样细胞和内皮细胞中的光磷酸化将通过对MRSA的耐药性降低MRSA病理 毒素介导的杀伤通过增强的外泌体释放。 为了测试这一点，我们将开发一种鼠标模型，该模型具有髓样或内皮细胞特异性LXRαS196A 敲入小鼠，并比较MRSA感染后血液中血液中的死亡率和外泌体丰度与WT LXRα小鼠和全局LXRαS196A小鼠。我们还将从 野生型和LXRαS196A小鼠以及MRSA感染后对基因表达的测量对揭示 通过LXRαS196磷酸化调节的基因和途径，可以操纵以进行预防和 治疗目的。我们还将测试是否促进非 - 野生型LXRα的磷酸化形式可以保护野生型小鼠和人PBMC免受致命的MRSA 感染。成功完成目标将确定LXRα辐射是否代表可触发的 由于其能够降低炎症基因表达的能力而治疗MRSA的靶标。