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Intercellular mechanisms of microglia activation in diet-induced obesity

饮食诱导肥胖中小胶质细胞激活的细胞间机制

基本信息

批准号：
10287448
负责人：
Sabrina Diano
金额：
$ 40.5万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10287448
关键词：
Administrative Supplement Adult Affect Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid Proteins Behavior Behavioral Body Weight Brain Cells Cellular Metabolic Process Chronic Data Dendritic Spines Development Diabetes Mellitus Diet Event Exposure to Feeding behaviors Female Funding Genetic Grant High Fat Diet Hippocampus (Brain)Histologic Histology Homeostasis Hypothalamic structure Immune response Impairment Inflammation Inflammatory Response Mediating Metabolic Metabolic Diseases Metabolism Microglia Mitochondria Mus Neuraxis Neurodegenerative Disorders Neurons Non-Insulin-Dependent Diabetes Mellitus Obese Mice Obesity Peptides Phagocytosis Phase Play Predisposition Presynaptic Terminals Process Publishing Regulation Risk Factors Role Spinal Cord Stress Structure Synapses Synaptic plasticity Testing Time UCP2 protein United States National Institutes of Health Weight Gain Work behavioral study combat diet-induced obesity experimental study feeding glucose metabolism histological studies insight male mitochondrial metabolism monocyte mouse model neural circuit neuroinflammation neuronal circuitry novel obesity risk parent grant presenilin-1 prevent response tau Proteins tau-1 treatment strategy

项目摘要

This is an administrative supplement request (PA-18-591) in response to NOT-AG-20-034 (Alzheimer's -focused Administrative supplements for NIH grants that are not focused on Alzheimer's disease) to our ongoing NIH grant 1R01DK120321-03 entitled “Intracellular mechanisms of microglia activation in diet-induced obesity”. This project aims to unmask the role of uncoupling protein 2 (UCP2)-mediated mitochondrial dynamics in microglia activation in the central regulation of energy homeostasis in order to develop better strategies for the treatment of metabolic disorders, such as obesity and type 2 diabetes. There are no Alzheimer’s Disease-related studies proposed in this grant. In response to NOT-AG-20-034, we request funds to test the hypothesis that UCP2-dependent microglia activation and neuroinflammation may impact the onset of the development of Alzheimer’s disease (AD) in genetic mouse model of AD by affecting histological and behavioral changes. Our preliminary studies show that inhibiting UCP2-dependent microglia activation in mice exposed to HFD feeding prevents neuroinflammation (microgliosis), protects from the development of metabolic disorders, such as obesity and type 2 diabetes, and also prevents changes in behaviors and hippocampal structure that are associated with aging and AD. As aging and obesity are risk factors for the development of neurodegenerative disorders such as Alzheimer’s disease (AD), we hypothesize that HFD-induced UCP2-dependent microglia activation plays a role in the onset of the development of AD and inhibition of this mechanism, by reducing chronic neuroinflammation, prevents and/or delays the onset of cortical and hippocampal histological and behavioral changes in AD. Thus, in this supplement we propose to assess the effect of selective and inducible deletion of UCP2 in microglial cells on the histology and behavior of AD mice [5xFAD mice (B6.Cg- Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas/Mmjax; Oakley H et al., 2006)] exposed to either standard chow diet or HFD, at different time points. Several littermate mice will be used as controls. Both male and female mice will be studied. Behavioral and histological studies will be performed at different time points to assess the role of microglia in the onset of AD development in this AD mouse model. The execution of these studies will deliver novel insights into the role of microglia and metabolism in AD.

这是针对NOT-AG-20-034(关注阿尔茨海默氏症)的行政补充请求(PA-18-591 对非阿尔茨海默病的NIH拨款的行政补充)到我们正在进行的NIH拨款 1R01DK120321-03，标题为“饮食诱导的肥胖中小胶质细胞激活的细胞内机制”。这该项目旨在揭示解偶联蛋白2(UCP2)介导的小胶质细胞线粒体动力学的作用激活能量平衡的中枢调节，以便制定更好的治疗策略代谢紊乱，如肥胖症和2型糖尿病。目前还没有与阿尔茨海默病相关的研究在这项拨款中提议的。为了回应NOT-AG-20-034，我们请求资金来测试UCP2依赖的小胶质细胞的假设激活和神经炎症可能影响阿尔茨海默病(AD)的发病影响组织学和行为学改变的遗传性阿尔茨海默病小鼠模型。我们的初步研究表明抑制高脂饲料喂养小鼠UCP2依赖的小胶质细胞活化可预防神经炎症 (小胶质细胞增多症)，防止代谢紊乱的发展，如肥胖和2型糖尿病，以及还可以防止与衰老和AD相关的行为和海马体结构的变化。随着年龄的增长肥胖是阿尔茨海默病等神经退行性疾病发展的危险因素 (AD)，我们假设HFD诱导的UCP2依赖的小胶质细胞激活在高血压的发病中起作用。阿尔茨海默病的发展和抑制这一机制，通过减少慢性神经炎症，预防和/或延缓大鼠大脑皮质和海马区组织学和行为学改变的发生广告。因此，在这份补充材料中，我们建议评估选择性和可诱导的UCP2缺失对小胶质细胞的影响。细胞对AD小鼠组织学和行为学的影响[5xFAD小鼠(B6.Cg- TG(APPSwFlLon，PSEN1*M146L*L286V)6799Vas/Mmjax；Oakley H等人，2006)] 饮食或高脂饮食，在不同的时间点。将用几只产仔小鼠作为对照。无论是男性还是女性将对老鼠进行研究。将在不同的时间点进行行为和组织学研究，以评估小胶质细胞在阿尔茨海默病小鼠模型中的作用。这些研究的执行将对小胶质细胞和新陈代谢在阿尔茨海默病中的作用提供新的见解。