Mitochondria and anesthetic-induced developmental neurotoxicity
Mitochondria and anesthetic-induced developmental neurotoxicity
批准号:
10551963
负责人:
Xiaowen Bai
金额:
$39.0万
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-09-01 至 2028-06-30
关键词:
Acute Brain InjuriesAddressAgeAnesthesia proceduresAnestheticsAnimalsAreaBehaviorBehavioralCRISPR/Cas technologyCell DeathCessation of lifeChildCognitive deficitsDataEpidemiologyGeneral anesthetic drugsGenesGoalsHumanImpaired cognitionImpairmentInjuryInvestigationKnowledgeLinkMediatingMitochondriaMolecularMusNeuronsNeurosciencesOperative Surgical ProceduresPathway interactionsPost-Transcriptional RegulationProblem behaviorPublic HealthResearchSignal TransductionTransgenic MiceUnited States Food and Drug AdministrationUntranslated RNAbrain cellcell typedevelopmental neurotoxicitygain of functionhigh throughput analysisinduced pluripotent stem cellinnovationloss of functionmitochondrial dysfunctionmouse modelmulti-photonmultiple omicsneuroprotectionneurotoxicneurotoxicityneurotransmissionnovelpreventprogramsreal-time imagessingle-cell RNA sequencingsmall moleculestem cell modeltherapeutically effectivetool
中文摘要
项目总结
数以百万计的儿童接受外科手术的全身麻醉剂(GAS)。来自人类的新证据
流行病学和动物研究表明,短效全身麻醉药可导致急性脑损伤
损伤,导致长期的认知缺陷和行为问题。2016年,美国食品和药物管理局
美国政府就GA对未成年儿童的潜在神经毒性效应发出警告
三。由于GA在许多手术中是必要的,避免使用通常是不可能的。因此,理解如何
麻醉药引起的神经毒性在公共卫生中至关重要,特别是为了有效地
可以开发神经保护策略。一个有希望的研究领域是线粒体--AS
神经元对能量的需求很高,特别容易因功能障碍而受伤和死亡。
线粒体。然而,尽管对麻醉剂引起的发育神经毒性进行了广泛的研究
(AIDN)在过去几十年中所做的,线粒体损伤导致神经元的机制
信号去监管化和细胞死亡仍不清楚。线粒体损伤与线粒体损伤的因果关系
麻醉剂引起的长期行为异常尚未被探索。为了解决上述问题,
GAP,在我们的初步研究中,我们发现麻醉药对脑线粒体有毒性
发育中的小鼠和人脑细胞。我们的数据还表明,调节失调的非
在麻醉剂诱导的线粒体功能受损中编码RNA。因此,这一计划的首要目标是
通过对线粒体功能的研究,继续填补线粒体在麻醉剂无毒方面的知识空白
AIDN线粒体调控新的分子机制及其神经保护的研究进展
以线粒体为目标的方法。根据我们实验室最近的研究和初步发现,我们的
拟议的方案将侧重于以下三个独立的研究领域:1)确定功能和
麻醉诱导的认知功能障碍中线粒体信号的脑细胞类型特异性机制
不正常的行为。2)描述了线粒体转录后调控的新机制
信号和功能在AIDN中受到调节。3)探讨小分子药物对AIDN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进行这些研究。
通过CRISPR-Cas9基因编辑获得多潜能干细胞模型。此外,该程序将使用
创新、尖端的实验神经科学工具、无偏见的多组学方法(例如,基因获得-
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,这可能导致预防幼儿AIDN的有效疗法。
英文摘要
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.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
lncRNAs and Anesthetic-Induced Developmental Neurotoxicity
-
批准号:10382813
-
项目类别:
-
资助金额:$21.7万
-
财政年份:2014
-
负责人:Xiaowen Bai
-
依托单位:
lncRNAs and Anesthetic-Induced Developmental Neurotoxicity
-
批准号:10404038
-
项目类别:
-
资助金额:$32.73万
-
财政年份:2014
-
负责人:Xiaowen Bai
-
依托单位:
microRNAs and Anesthetic-Induced Developmental Neurotoxicity
-
批准号:8670138
-
项目类别:
-
资助金额:$29.07万
-
财政年份:2014
-
负责人:Xiaowen Bai
-
依托单位:
lncRNAs and Anesthetic-Induced Developmental Neurotoxicity
-
批准号:10172919
-
项目类别:
-
资助金额:$32.73万
-
财政年份:2014
-
负责人:Xiaowen Bai
-
依托单位:
lncRNAs and Anesthetic-Induced Developmental Neurotoxicity
-
批准号:9980423
-
项目类别:
-
资助金额:$32.73万
-
财政年份:2014
-
负责人:Xiaowen Bai
-
依托单位:
microRNAs and Anesthetic-Induced Developmental Neurotoxicity
-
批准号:9024592
-
项目类别:
-
资助金额:$29.07万
-
财政年份:2014
-
负责人:Xiaowen Bai
-
依托单位:
海外基金