Molecular Mechanisms Underlying Obesity-related Memory Deficits

肥胖相关记忆缺陷的分子机制

基本信息

批准号：
10295777
负责人：
Catrina Sims Robinson
金额：
$ 32.7万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-01 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10295777
关键词：
Address Adolescent Adult Alzheimer&apos s Disease Animal Model Blood Blood - brain barrier anatomy Blood Vessels Brain Catheterization Cells Centers for Disease Control and Prevention (U.S.)Cerebrospinal Fluid Cognition Disorders Cognitive deficits Data Development Goals High Fat Diet Hippocampus (Brain)Impaired cognition Impairment Infusion procedures Insulin Insulin Receptor Label Laboratories Lead Link Measures Mediating Memory Memory impairment Microdialysis Molecular Mus Neuraxis Obesity Obesity Epidemic Overweight Pathologic Patients Peripheral Public Health Receptor Signaling Reducing diet Research Resistance Risk Role Signaling Protein Techniques Testing Transgenic Mice Vascular Endothelial Cell Vascular Endothelium Work aging brain aging population base brain cell cognitive function design diet-induced obesity economic cost improved in vivo innovation insulin signaling long term memory memory process mild cognitive impairment nervous system disorder novel therapeutics obese person prevent receptor receptor expression targeted treatment therapy development uptake

项目摘要

Project Summary/Abstract There is a fundamental gap in understanding the molecular mechanisms underlying central nervous system (CNS) insulin transport. This represents an important gap due to the importance of CNS insulin in memory. The long-term goal is to understand the impact of obesity on both normal and pathological brain aging. The objective of this particular application is to investigate the effect of high-fat diet (HFD) induced obesity on CNS insulin and cognitive function. Obesity-induced effects on CNS insulin transport may render the brain susceptible to memory impairment. The central hypothesis is that HFD reduces hippocampal insulin transport, thereby impairing cognitive function. This hypothesis is based on preliminary data produced in the applicant's laboratory. The rationale for the proposed research is that understanding the impact of CNS insulin on brain function will set the stage for the development of innovative approaches to mitigate obesity-associated cognitive decline. Thus, this hypothesis will be tested by pursing two specific aims: 1) test hypothesis that HFD reduces hippocampal insulin transport and 2) test hypothesis that impairing CNS insulin transport results in cognitive deficits. Under Aim 1, molecular techniques in HFD mice will be utilized to evaluate the uptake of insulin into the hippocampus. In addition, the changes in insulin receptor expression and signaling proteins will be evaluated in isolated hippocampal microvessels, which represent the blood brain barrier. Under the second aim, a transgenic mouse lacking the insulin receptor specifically in vascular endothelial cells will be used to evaluate the role of the insulin receptor in CNS insulin transport and the impact on cognitive function. The approach is innovative, because it utilizes an animal model specifically designed to understand the mechanisms underlying obesity-related impairments in CNS insulin transport and its impact on cognitive function. The proposed research is significant, because it is expected it is expected to lead to the development of targeted therapies to delay or prevent cognitive decline. Ultimately, the results of this work may also be useful in improving cognitive function associated with neurological disorders such as Mild Cognitive Impairment or Alzheimer's disease.

项目概要/摘要对中枢神经系统分子机制的理解存在根本差距（中枢神经系统）胰岛素转运。由于中枢神经系统胰岛素在记忆中的重要性，这代表了一个重要的差距。长期目标是了解肥胖对正常和病理性大脑衰老的影响。这此特定应用的目的是研究高脂饮食 (HFD) 引起的肥胖对中枢神经系统的影响胰岛素和认知功能。肥胖对中枢神经系统胰岛素转运的影响可能会损害大脑容易出现记忆障碍。核心假设是 HFD 会减少海马胰岛素转运，从而损害认知功能。该假设基于申请人的初步数据实验室。拟议研究的基本原理是了解中枢神经系统胰岛素对大脑的影响功能将为开发创新方法奠定基础，以减轻与肥胖相关的疾病认知能力下降。因此，该假设将通过追求两个具体目标来检验：1）检验 HFD 的假设减少海马胰岛素转运，2) 检验损害中枢神经系统胰岛素转运导致的假设认知缺陷。在目标 1 下，将利用 HFD 小鼠的分子技术来评估胰岛素进入海马体。此外，胰岛素受体表达和信号蛋白的变化将在代表血脑屏障的分离海马微血管中进行评估。第二下目标是，血管内皮细胞中特异性缺乏胰岛素受体的转基因小鼠将被用于评估胰岛素受体在中枢神经系统胰岛素转运中的作用及其对认知功能的影响。这该方法是创新的，因为它利用了专门设计来理解的动物模型肥胖相关中枢神经系统胰岛素转运损伤的机制及其对认知的影响功能。拟议的研究意义重大，因为预计它将导致发展延缓或预防认知能力下降的靶向治疗。最终，这项工作的结果也可能是有助于改善与神经系统疾病（例如轻度认知障碍）相关的认知功能或阿尔茨海默病。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Hyperinsulinemia alters insulin receptor presentation and internalization in brain microvascular endothelial cells.

DOI：
10.1177/14791641221118626
发表时间：
2022-07
期刊：
DIABETES & VASCULAR DISEASE RESEARCH
影响因子：
2.4
作者：
Watson, Luke S.;Wilken-Resman, Brynna;Williams, Alexus;DiLucia, Stephanie;Sanchez, Guadalupe;McLeod, Taylor L.;Sims-Robinson, Catrina
通讯作者：
Sims-Robinson, Catrina

Hyperinsulinemia Impairs Clathrin-Mediated Endocytosis of the Insulin Receptor and Activation of Endothelial Nitric Oxide Synthase in Brain Endothelial Cells.

DOI：
10.3390/ijms241914670
发表时间：
2023-09-28
期刊：
International journal of molecular sciences
影响因子：
5.6
作者：
DiLucia SG;Kendrick BJ;Sims-Robinson C
通讯作者：
Sims-Robinson C

Transcutaneous auricular vagus nerve stimulation (taVNS) decreases heart rate acutely in neonatal rats.

经皮耳迷走神经刺激（taVNS）可急剧降低新生大鼠的心率。

DOI：
10.1016/j.brs.2023.08.018
发表时间：
2023
期刊：
Brain stimulation
影响因子：
7.7
作者：
Gail,MelanieW;Sims-Robinson,Catrina;Boger,Heather;Ergul,Adviye;Mukherjee,Rupak;Jenkins,DorotheaD;George,MarkS
通讯作者：
George,MarkS

Brain-Derived Neurotrophic Factor and Nerve Growth Factor Therapeutics for Brain Injury: The Current Translational Challenges in Preclinical and Clinical Research.