Targeting neuronal Drp1-Fis1 interactions to mediate glucocorticoid-induced pathologies

靶向神经元 Drp1-Fis1 相互作用介导糖皮质激素诱导的病理

• 批准号: 10624062
• 负责人: Fiona E. Hollis
• 金额: $ 20.74万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10624062
• 关键词: Adult; Behavioral; Cell Survival; Chronic; Chronic stress; Development; Dynamin; Feeling; Functional disorder; Glucocorticoids; Health; Inflammasome; Inflammation; Link; Mediating; Mitochondria; Neurons; Organelles; Outcome; Outer Mitochondrial Membrane; Pathology; Proteins; Reporting; Role; Stress; Testing; behavioral outcome; cytokine; prevent; receptor; recruit; response; targeted treatment

Nearly 80% of adults report feeling high levels of stress in their daily lives. As chronic stress exposure is associated with negative health outcomes, understanding the effects of this stress exposure is crucial to preventing the development of downstream pathologies. Mitochondria are dynamic organelles that have roles in a number of functions that are crucial for cell survival. One such function includes the synthesis and release of glucocorticoids in response to stress exposure. Interestingly, glucocorticoids can also impact mitochondrial function, with high levels inducing dysfunction and mitochondrial fragmentation. Mitochondrial fragmentation has been shown to activate inflammasomes and increase levels of proinflammatory cytokines, which have been linked to negative behavioral outcomes linked to stress. Mitochondrial fragmentation relies in part on a fission factor called Dynamin-related protein 1 (Drp1) and its interactions with its receptors on the mitochondrial outer membrane. While studies have shown that chronic stress induces fragmentation, the precise interactions between Drp1, its receptors, and chronic unpredictable stress remains unclear. Our studies will test whether chronic unpredictable stress induces excessive mitochondrial fragmentation via the elevation of glucocorticoids that increase Drp1 recruitment to the mitochondrial outer membrane in a receptor-specific manner. We will then examine whether disruption of these specific Drp1-receptor interactions can prevent mitochondrial fragmentation and subsequent inflammation and downstream behavioral alterations.

近80%的成年人报告在日常生活中感到高度压力。就像慢性压力暴露一样