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Metabolomic characterization of normal aging and Alzheimer's disease under anesthesia- surgery stimuli

麻醉手术刺激下正常衰老和阿尔茨海默病的代谢组学特征

基本信息

批准号：
10350570
负责人：
Leo L Cheng
金额：
$ 78.67万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-15 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10350570
关键词：
AD transgenic mice Aftercare Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease diagnosis Alzheimer&apos s disease patient Anesthesia procedures Animal Behavior Animal Model Animals Anti-Inflammatory Agents Blood Brain Brain region Clinic Clinical Clinical Protocols Cyclosporine Development Diffusion Magnetic Resonance Imaging Electron Microscope Evaluation Foundations Functional Magnetic Resonance Imaging Gluconeogenesis Glucose Goals Homeostasis Hour Human Image Immunochemistry Impairment Individual Intervention Knock-out Label Lead Longevity Magnetic Resonance Imaging Magnetic Resonance Spectroscopy Measurement Measures Metabolic Methods Mitochondria Monitor Mus Onset of illness Operative Surgical Procedures Organ Pathogenesis Pathway interactions Patients Predisposition Preventive Procedures Protocols documentation Rest Serum Stimulus Technology Testing Time Tissue Harvesting Tissues Training Transgenic Organisms Translating Validation Vitamin K 2 Wild Type Mouse arm base behavior test brain tissue cohort design in vivo in vivo imaging in vivo magnetic resonance spectroscopy metabolomics mitochondrial dysfunction morris water maze mouse model multimodality myelination neuroinflammation noninvasive diagnosis normal aging novel success tool

项目摘要

We propose to quantify aging- and AD-associated brain and blood metabolic changes through ex vivo and in vivo multimodality MR measurements in mouse models after an AD-promoting stimuli, anesthesia-surgery, with-or-without preventive, protective treatments. This approach recognizes that AD onset, pathogenesis and progression must produce alterations in the overall metabolic status, or metabolomics, of brain and other organs in AD patients, as compared with normal homeostasis in healthy individuals, and our understanding of the urgent need to develop non-invasive AD diagnosis tools. In the three proposed Aims, we will (1) Characterize age-associated metabolomic changes ex vivo using tissues from different brain regions and blood serum obtained from wild-type and AD mice after administration of anesthesia-surgery stimuli; (2) Develop multimodality in vivo MR protocols for non-invasive evaluations of age- and AD-associated brain metabolic changes induced by anesthesia-surgery stimuli; and (3) Investigate the effect of an AD protective intervention on metabolomic changes after administration of anesthesia-surgery stimuli. The success of this project will lead us to establish translational protocols that can guide and interpret multimodality in vivo MR imaging results by obtaining accurate ex vivo MRS, EM, and immunochemistry measurements in the proposed animal models, and translating these findings into clinical protocols for human AD non-invasive diagnosis.

我们建议通过体外和体内实验来量化衰老和AD相关的大脑和血液代谢变化。在AD促进刺激，麻醉手术，不管有没有预防性保护性治疗这种方法认识到AD的发病、发病机制和疾病的进展必然会导致大脑和其他组织的整体代谢状态或代谢组学的改变。与健康个体的正常稳态相比，我们对AD患者的器官的了解迫切需要开发非侵入性AD诊断工具。在这三个目标中，我们将（1）使用来自不同脑区和血液的组织离体表征年龄相关的代谢组学变化在给予麻醉-手术刺激后从野生型和AD小鼠获得的血清;（2）开发用于年龄和AD相关脑代谢非侵入性评价的多模态体内MR方案麻醉-手术刺激引起的变化;（3）研究AD保护性干预的效果对麻醉手术刺激后代谢组学变化的影响。该项目的成功将引导我们建立可以指导和解释多模态体内MR成像结果的翻译协议通过在所提出的动物模型中获得精确的离体MRS、EM和免疫化学测量，并将这些发现转化为人类AD非侵入性诊断的临床方案。