Mitochondria and anesthetic-induced developmental neurotoxicity

线粒体和麻醉诱导的发育神经毒性

• 批准号: 10551963
• 负责人: Xiaowen Bai
• 金额: $ 39万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10551963
• 关键词: Acute Brain Injuries; Address; Age; Anesthesia procedures; Anesthetics; Animals; Area; Behavior; Behavioral; CRISPR/Cas technology; Cell Death; Cessation of life; Child; Cognitive deficits; Data; Epidemiology; General anesthetic drugs; Genes; Goals; Human; Impaired cognition; Impairment; Injury; Investigation; Knowledge; Link; Mediating; Mitochondria; Molecular; Mus; Neurons; Neurosciences; Operative Surgical Procedures; Pathway interactions; Post-Transcriptional Regulation; Problem behavior; Public Health; Research; Signal Transduction; Transgenic Mice; United States Food and Drug Administration; Untranslated RNA; brain cell; cell type; developmental neurotoxicity; gain of function; high throughput analysis; induced pluripotent stem cell; innovation; loss of function; mitochondrial dysfunction; mouse model; multi-photon; multiple omics; neuroprotection; neurotoxic; neurotoxicity; neurotransmission; novel; prevent; programs; real-time images; single-cell RNA sequencing; small molecule; stem cell model; therapeutically effective; tool

PROJECT SUMMARY Millions of children receive general anesthetics (GAs) for surgical procedures. Emerging evidence from human epidemiologic and animal studies suggest that short acting general anesthetic drugs can cause acute brain injury, leading to long-term cognitive defects and behavioral problems. In 2016, the US Food and Drug Administration issued a warning about the potential neurotoxic effects of GA exposure in children under age three. As GA use is necessary for many surgeries, avoidance is often impossible. Thus, understanding how anesthetics induce neurotoxicity is of critical importance in public health, especially so that effective neuroprotective strategies can be developed. One promising area of investigation is mitochondria -- as neurons have high energy requirements, they are especially vulnerable to injury and death from dysfunctional mitochondria. However, despite the extensive research of anesthetic-induced developmental neurotoxicity (AIDN) done during the last decades, mechanisms by which mitochondrial impairment leads to neuronal signaling deregulation and cell death remain unclear. Causative relationship between mitochondrial injury and anesthetic-induced long-term behavioral abnormalities has not been explored. To address the aforementioned gap, in our preliminary studies we investigated and found that anesthetics were toxic to mitochondria in developing mouse and human brain cells. Our data also suggest the regulative function of dysregulated non- coding RNAs in anesthetic-induced impaired mitochondrial function. Thus, the overarching goal of this program is to continue to fill the gap of mitochondrial knowledge in anesthetic nontoxicity by investigating the functions and novel regulatory molecular mechanisms of mitochondria in AIDN as well as developing neuroprotective approaches targeting mitochondria. Extending upon our lab's recent research and preliminary findings, our proposed program will focus on the following three independent research areas: 1) Determine functions and brain cell type-specific mechanisms of mitochondrial signaling in anesthetic-induced cognitive dysfunction and abnormal behaviors. 2) Delineate novel posttranscriptional regulation mechanisms by which mitochondrial signaling and functions are regulated in AIDN. 3) Investigate neuroprotective effect of small molecules in AIDN. We will conduct these investigations using both transgenic mouse models and similar human induced pluripotent stem cell models obtained via CRISPR-Cas9 gene editing. Furthermore, this program will use innovative, cutting-edge experimental neuroscience tools, unbiased multi-omic approaches (e.g., gene gain- and loss-of function, multiphoton real time imaging, single-cell RNA sequencing, and high-throughput analysis of neuronal activities). The proposed studies will facilitate a better understanding of GA-driven mitochondrial dysfunction, which may lead to effective therapeutics for preventing AIDN in young children.

项目概要 数百万儿童在手术过程中接受全身麻醉 (GA)。来自人类的新证据 流行病学和动物研究表明，短效全身麻醉药物可引起急性脑损伤 伤害，导致长期的认知缺陷和行为问题。 2016年，美国食品药品监督管理局 政府就 GA 暴露对 1 岁以下儿童的潜在神经毒性作用发出警告 三。由于许多手术都需要使用 GA，因此通常无法避免。因此，了解如何 麻醉剂引起的神经毒性对于公共卫生至关重要，尤其是有效的麻醉剂 可以制定神经保护策略。线粒体是一个有希望的研究领域—— 神经元有很高的能量需求，它们特别容易因功能失调而受伤和死亡 线粒体。然而，尽管对麻醉引起的发育神经毒性进行了广泛的研究 （AIDN）在过去几十年中完成了线粒体损伤导致神经元损伤的机制 信号放松管制和细胞死亡仍不清楚。线粒体损伤与线粒体损伤之间的因果关系 麻醉引起的长期行为异常尚未得到探索。为了解决上述问题 差距，在我们的初步研究中，我们调查并发现麻醉剂对线粒体有毒 开发小鼠和人类的脑细胞。我们的数据还表明，失调的非- 麻醉引起的线粒体功能受损中编码RNA。因此，该计划的总体目标 是通过研究线粒体的功能来继续填补麻醉无毒性方面线粒体知识的空白 AIDN 中线粒体的新调控分子机制以及开发神经保护剂 针对线粒体的方法。扩展我们实验室最近的研究和初步发现，我们的 拟议的计划将重点关注以下三个独立研究领域：1）确定功能和 麻醉引起的认知功能障碍中线粒体信号传导的脑细胞类型特异性机制 异常行为。 2）描绘线粒体的新转录后调节机制 信号传导和功能在 AIDN 中受到调节。 3) 研究AIDN中小分子的神经保护作用。 我们将使用转基因小鼠模型和类似的人类诱导模型来进行这些研究 通过 CRISPR-Cas9 基因编辑获得的多能干细胞模型。此外，该程序将使用 创新、尖端的实验神经科学工具、公正的多组学方法（例如基因增益） 和功能丧失、多光子实时成像、单细胞 RNA 测序和高通量分析 神经元活动）。拟议的研究将有助于更好地理解 GA 驱动的线粒体 功能障碍，这可能会导致预防幼儿 AIDN 的有效治疗方法。