Tau/P-Tau as Biomarkers of Anesthesia- and Surgery-Induced Cognitive Impairment in a Murine Model

Tau/P-Tau 作为小鼠模型中麻醉和手术引起的认知障碍的生物标志物

基本信息

批准号：
9899748
负责人：
Zhongcong Xie
金额：
$ 36.55万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-22 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9899748
关键词：
ARHGEF5 gene Abdomen Affect Age Anesthesia procedures Anesthetics Animal Model Applications Grants Area Attenuated Behavioral Paradigm Biological Assay Biological Markers Blood Brain Caring Cerebrospinal Fluid Child Clinical Clinical Trials Communities Diagnosis Epitopes Funding Opportunities Health Human Impaired cognition In Vitro Individual Intellectual functioning disability Intervention Knock-out Knockout Mice Knowledge Lead Lithium Mass Spectrum Analysis Measures Medical Microtubules Migration Assay Mission Mus National Institute of Child Health and Human Development Neurons Operative Surgical Procedures Outcome Population Study Postoperative Period Process Research Risk Technology Testing Translating Urine Validation Western Blotting biomarker validation brain tissue cell motility cognitive function dentate gyrus desflurane disability in vivo inhibitor/antagonist innovation interest migration mouse model nanobiosensor nerve stem cell neurodevelopment neurogenesis postnatal public health relevance screening sevoflurane subventricular zone tau Proteins tau-1 validation studies young adult

项目摘要

DESCRIPTION (provided by applicant): This R01 application is submitted to the funding opportunity announcement (PAR-13-195). Millions of children have surgery and anesthesia each year. Recent population studies have suggested that children who undergo anesthesia and surgery at an earlier age could have an increased risk for neurodevelopment disabilities (e.g., cognitive impairment). It is therefore urgent to perform studies in this new and under-investigated area: anesthesia- and surgery-induced cognitive impairment in children. However, thus far, no biomarker of such cognitive impairment has been developed. This gap in knowledge impedes the progress of such research. Therefore, we have proposed to develop and validate biomarkers in mouse models that can later be used to inform and effectively translate to clinical trials in children to study anesthesia- and surgery-induced cognitive impairment. Consistent with the notion that phosphorylated Tau (P-Tau) and neurogenesis contribute to cognitive function, our Preliminary studies show that anesthetic sevoflurane can increase levels of brain P-Tau, inhibit neurogenesis, cause cognitive impairment and increase blood Tau levels in young mice. Therefore, we hypothesize that Tau and P-Tau in blood and urine serve as the biomarkers for anesthesia- and surgery-induced cognitive impairment in young mice, and P-Tau inhibits the migration of neural progenitor cells (NPCs) by de-stabilizing their microtubules. Using both in vitro and in vivo approaches, and the innovative nano biosensor technology, we will test our hypothesis with three Specific Aims. In Aim 1, we will use mass spectrometry, Western blot and nano biosensor technology to screen and then identify the elevation of Tau (soluble and insoluble) and specific P-Tau in mouse brain tissues and cerebrospinal fluid (CSF) following the particular anesthesia and surgery. We will also determine the associated cognitive function in the mice. In Aim 2, we will use nano biosensor technology to show that there is elevation of Tau and specific P-Tau (same as those in the brain and CSF) in the blood and urine following the anesthesia and surgery in mice. Then, in the interventional validation studies, we will determine whether lithium and knockout (KO) of Tau (employing Tau KO mice) can mitigate the anesthesia- and surgery-induced cognitive impairment, and attenuate the elevation of Tau and P-Tau in the blood and urine of young mice. In the mechanistic validation studies (Aim 3), we will assess whether anesthesia- and surgery-induced increases in P-Tau will damage microtubule stability of the NPCs (in vitro) and slow down the NPCs migration (in vivo and in vitro). We will determine whether lithium and KO of Tau can rescue these effects. Translationally, this project would develop biomarkers for anesthesia- and surgery-induced cognitive impairment in young mice, which could later be used in children. Scientifically, this project would elucidate an innovative mechanism by which Tau affects NPCs migration. The results of this project would ultimately lead to safer anesthesia care and better postoperative outcomes for children.

描述（由申请人提供）：此 R01 申请已提交给资助机会公告 (PAR-13-195)。最近的人口研究表明，每年有数百万儿童接受麻醉和手术。年龄可能会增加神经发育障碍（例如认知障碍）的风险，因此迫切需要在麻醉和手术引起的儿童认知障碍这一新领域进行研究。这种认知障碍的认识阻碍了此类研究的进展，因此，我们建议在小鼠模型中开发和验证生物标志物，这些标志物随后可用于指导并有效转化为儿童临床试验以研究麻醉。 - 和手术引起的认知障碍，与磷酸化 Tau (P-Tau) 和神经发生有助于认知功能的观点一致，我们的初步研究表明，麻醉剂七氟烷可以增加大脑 P-Tau 的水平，抑制神经发生，导致认知功能障碍。因此，我们研究血液和尿液中的 Tau 和 P-Tau 作为年轻小鼠麻醉和手术引起的认知障碍的生物标志物，并且 P-Tau 抑制 Tau 的迁移。通过使用体外和体内方法以及创新的纳米生物传感器技术来破坏神经祖细胞（NPC）的微管，我们将通过三个具体目标来检验我们的假设。质谱、蛋白质印迹和纳米生物传感器技术筛选并鉴定特定麻醉和手术后小鼠脑组织和脑脊液 (CSF) 中 Tau（可溶性和不可溶性）和特定 P-Tau 的升高。在目标 2 中，我们将使用纳米生物传感器技术来显示血液和尿液中 Tau 和特定 P-Tau（与大脑和脑脊液中的相同）的升高。然后，在小鼠麻醉和手术后，我们将确定锂和 Tau 敲除（KO）（使用 Tau KO 小鼠）是否可以减轻麻醉和手术引起的认知障碍，并减轻认知障碍。在机制验证研究（目标 3）中，我们将评估麻醉和手术引起的 P-Tau 增加是否会损害微管的稳定性。 NPC（体外）并减缓 NPC 迁移（体内和体外）我们将确定锂和 Tau 的 KO 是否可以挽救这些影响，该项目将开发用于麻醉和手术引起的认知障碍的生物标志物。从科学上讲，该项目将阐明 Tau 影响 NPC 迁移的创新机制，最终将为儿童带来更安全的麻醉护理和更好的术后结果。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（1）

Sevoflurane Induces a Cyclophilin D-Dependent Decrease of Neural Progenitor Cells Migration.

七氟烷诱导亲环素 D 依赖性神经祖细胞迁移减少。

DOI：
发表时间：
2023-04-04
期刊：
影响因子：
5.6
作者：
Lu, Pan;Liang, Feng;Dong, Yuanlin;Xie, Zhongcong;Zhang, Yiying
通讯作者：
Zhang, Yiying

Mild Hypothermia Attenuates the Anesthetic Isoflurane-Induced Cytotoxicity.

轻度低温可减轻麻醉剂异氟烷引起的细胞毒性。

DOI：
发表时间：
2017
期刊：
影响因子：
0
作者：
Li, Cheng;Dong, Yuanlin;Chen, Dan;Xie, Zhongcong;Zhang, Yiying
通讯作者：
Zhang, Yiying

Testosterone attenuates sevoflurane-induced tau phosphorylation and cognitive impairment in neonatal male mice.

睾酮可减弱新生雄性小鼠七氟醚诱导的 tau 蛋白磷酸化和认知障碍。

DOI：
10.1016/j.bja.2021.08.028
发表时间：
2021-10-01
期刊：
British journal of anaesthesia
影响因子：
9.8
作者：
Yongya Yang;Feng Liang;Jie Gao;Yuanlin Dong;Yiying Zhang;Guang Yang;S. Soriano;H. Feng;Zhon
通讯作者：
Zhon

Dexmedetomidine and Clonidine Attenuate Sevoflurane-Induced Tau Phosphorylation and Cognitive Impairment in Young Mice via α-2 Adrenergic Receptor.

右美托咪定和可乐定通过 α-2 肾上腺素受体减弱七氟烷诱导的 Tau 磷酸化和幼鼠认知障碍。