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.

这是对NOT-AG-20-034（阿尔茨海默氏症的响应，pa-18-591）的行政补充请求（PA-18-591）我们正在进行的NIH赠款的NIH赠款的行政补品 1R01DK120321-03标题为“饮食引起的肥胖症中小胶质细胞激活的细胞内机制”。这项目旨在揭示小胶质细胞中脱偶联蛋白2（UCP2）介导的线粒体动力学的作用为了制定更好的治疗策略，激活能量稳态的中央调节代谢性疾病，例如肥胖和2型糖尿病。没有阿尔茨海默氏病有关的研究在这笔赠款中提出。为了响应NOT-AG-20-034，我们要求资金测试UCP2依赖的小胶质细胞的假设激活和神经炎症可能会影响阿尔茨海默氏病（AD）发展的开始通过影响组织学和行为变化，AD的遗传小鼠模型。我们的初步研究表明暴露于HFD喂养的小鼠中抑制UCP2依赖的小胶质细胞激活可防止神经炎症（小胶质细胞增多），免受代谢性疾病的发展，例如肥胖和2型糖尿病，以及还可以防止与衰老和AD相关的行为和海马结构的变化。作为老化肥胖是神经退行性疾病（例如阿尔茨海默氏病）发展的危险因素（AD），我们假设HFD诱导的UCP2依赖性小胶质细胞激活在开始中起作用通过减少慢性神经炎症的发展AD的发展和抑制这种机制预防和/或延迟皮质和海马组织学和行为变化的发作广告。在这种补充中，我们建议评估UCP2在小胶质细胞中的选择性和诱导删除的效果 AD小鼠的组织学和行为的细胞[5XFAD小鼠（B6.CG-- TG（AppSwfllon，PSEN1*M146L*L286V）6799VAS/MMJAX; Oakley H等，2006）]暴露于任一标准在不同时间点，饮食或HFD。几只窝窝小鼠将用作对照。男性和女性将研究老鼠。行为和组织学研究将在不同的时间点进行评估在此AD小鼠模型中，小胶质细胞在AD开发开始中的作用。这些研究的执行将对小胶质细胞和代谢在AD中的作用进行新颖的见解。