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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R 01申请提交给资助机会公告（PAR-13-195）。每年有数百万儿童接受手术和麻醉。最近的人口研究表明，在较早年龄接受麻醉和手术的儿童可能会增加神经发育障碍的风险（例如，认知障碍）。因此，迫切需要在这一新的和研究不足的领域进行研究：麻醉和手术引起的儿童认知障碍。然而，迄今为止，尚未开发出这种认知障碍的生物标志物。这种知识上的差距阻碍了这种研究的进展。因此，我们建议在小鼠模型中开发和验证生物标志物，这些生物标志物随后可用于告知并有效地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，麻醉剂七氟烷可增加幼龄小鼠的脑P-Tau水平，抑制神经发生，导致认知障碍并增加血液Tau水平。因此，我们假设血液和尿液中的Tau和P-Tau作为麻醉和手术诱导的年轻小鼠认知障碍的生物标志物，P-Tau通过使其微管不稳定来抑制神经祖细胞（NPC）的迁移。使用体外和体内的方法，以及创新的纳米生物传感器技术，我们将测试我们的假设与三个具体目标。目的1：利用质谱、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（可溶性和不溶性）和特异性P-Tau的升高。我们还将确定小鼠的相关认知功能。在目标2中，我们将使用纳米生物传感器技术来显示在小鼠麻醉和手术后血液和尿液中存在Tau和特异性P-Tau（与脑和CSF中的那些相同）的升高。然后，在干预性验证研究中，我们将确定锂和Tau敲除（KO）（采用Tau KO小鼠）是否可以减轻麻醉和手术诱导的认知障碍，并减弱幼龄小鼠血液和尿液中Tau和P-Tau的升高。在机制验证研究（目的3）中，我们将评估麻醉和手术诱导的P-Tau增加是否会损害NPC的微管稳定性（体外）并减缓NPC迁移（体内和体外）。我们将确定锂和Tau的KO是否可以挽救这些效应。该项目将开发麻醉和手术诱导的年轻小鼠认知障碍的生物标志物，这些生物标志物随后可用于儿童。科学上，该项目将阐明Tau影响NPC迁移的创新机制。该项目的结果最终将为儿童带来更安全的麻醉护理和更好的术后结果。