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.

项目摘要/摘要理解中枢神经系统的分子机制存在根本的差距（CNS）胰岛素运输。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大脑衰老的影响。这该特定应用的目的是研究高脂饮食（HFD）肥胖对中枢神经系统的影响胰岛素和认知功能。肥胖引起的对中枢神经系统胰岛素运输的影响可能使大脑容易受到记忆障碍的影响。中心假设是HFD减少了海马胰岛素的转运，从而损害认知功能。该假设基于申请人的初步数据实验室。拟议研究的理由是了解中枢神经系统胰岛素对大脑的影响功能将为发展与肥胖相关的创新方法开发奠定基础认知能力下降。因此，将通过实现两个具体目的来检验该假设：1）检验HFD的假设减少海马胰岛素的转运和2）检验假设，损害CNS胰岛素转运导致的假设导致认知缺陷。在AIM 1下，将利用HFD小鼠中的分子技术评估胰岛素进入海马。另外，胰岛素受体表达和信号蛋白的变化将在孤立的海马微血管中进行评估，该微血管代表血脑屏障。第二目的，缺乏专门在血管内皮细胞中缺乏胰岛素受体的转基因小鼠将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以及对认知功能的影响。这方法具有创新性，因为它利用专门设计的动物模型来了解中枢神经系统胰岛素运输中与肥胖相关损伤的基础机制及其对认知的影响功能。拟议的研究很重要，因为预计有望导致发展有针对性的疗法延迟或预防认知能力下降。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氏病。

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.