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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.

这是响应 NOT-AG-20-034（阿尔茨海默氏病）的行政补充请求 (PA-18-591) 不针对阿尔茨海默氏病的 NIH 拨款的行政补充）是我们正在进行的 NIH 拨款的行政补充 1R01DK120321-03，标题为“饮食诱导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稳态的中央调节，以便制定更好的治疗策略代谢紊乱，例如肥胖和 2 型糖尿病。没有与阿尔茨海默病相关的研究在本次赠款中提出。为了回应 NOT-AG-20-034，我们请求资金来检验 UCP2 依赖性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）的发生通过影响组织学和行为变化来建立 AD 的遗传小鼠模型。我们的初步研究表明抑制 HFD 喂养小鼠 UCP2 依赖性小胶质细胞活化可预防神经炎症（小胶质细胞增生），防止代谢紊乱，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。随着老化肥胖和肥胖是阿尔茨海默病等神经退行性疾病的危险因素 (AD)，我们假设 HFD 诱导的 UCP2 依赖性小胶质细胞激活在通过减少慢性神经炎症，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生广告。因此，在本补充中，我们建议评估小胶质细胞中选择性和诱导性删除 UCP2 的效果细胞对 AD 小鼠组织学和行为的影响 [5xFAD 小鼠 (B6.Cg- Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas/Mmjax; Oakley H et al., 2006)]暴露于任一标准食物饮食或 HFD，在不同的时间点。几只同窝小鼠将用作对照。不论男性还是女性将研究小鼠。将在不同时间点进行行为和组织学研究以评估在此 AD 小鼠模型中，小胶质细胞在 AD 发生发展中的作用。这些研究的执行将对小胶质细胞和代谢在 AD 中的作用提供了新的见解。