Social Environment, Sympathetic Nervous System & Atherosclerosis in WHHL Rabbits

社会环境、交感神经系统

基本信息

批准号：
9084614
负责人：
PHILIP M MCCABE
金额：
$ 55.25万
依托单位：
UNIVERSITY OF MIAMI CORAL GABLES
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-23 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9084614
关键词：
Adrenergic Receptor Affect Agonistic Behavior Animal Model Animals Arterial Fatty Streak Atherosclerosis Attenuated Autonomic nervous system disorders Behavioral Blood Vessels Cardiovascular Diseases Cardiovascular system Catecholamines Cells Chronic Clinical Data Development Disease Disease Progression Disease model Emotional Stress Endothelium Functional disorder Genetic Genetic Determinism Goals Harvest Health Heart Diseases Hyperlipidemia Immune Immune system Individual Differences Infiltration Inflammation Intervention LOX gene Label Lead Lesion Link Lymphoid Tissue Measures Mediator of activation protein Molecular Myocardium Nerve Growth Factors Neuronal Plasticity Neurons Neurotrophic Tyrosine Kinase Receptor Type 1 New Zealand Oryctolagus cuniculus Oxidative Stress PTGS2 gene Pattern Peptides Peripheral Plasma Process Production Relaxation Research Research Personnel Risk Factors Role Series Severities Severity of illness Social Conditions Social Environment Social isolation Stress Superoxides Sympathetic Nervous System Time Tissues Varicosity Virus Replication Work attenuation base behavior influence biobehavior cytokine density emotional behavior emotional factor endothelial dysfunction hemodynamics innovation lymph nodes macrophage nerve supply novel novel strategies osmotic minipump prevent receptor expression research study response social vascular inflammation

项目摘要

DESCRIPTION (provided by applicant): The proposed research will examine the role of social/emotional factors in atherosclerosis, and attempt to establish mechanistic links among biobehavioral risk factors, molecular mediators and clinical disease progression. This will be accomplished through the use of the Watanabe Heritable Hyperlipidemic Rabbit (WHHL), a genetic animal model characterized by hyperlipidemia and severe atherosclerosis. We have demonstrated that social environment profoundly affects the course of disease in WHHLs, such that animals in stable relationships with littermates, as opposed to WHHLs in unstable social conditions or social isolation, showed a significant decrease in the progression of atherosclerosis. An unstable social environment, characterized by agonistic behavior and emotional stress, was associated with the development of severe, advanced atherosclerotic lesions. These findings suggest that biobehavioral factors are important in the progression of atherosclerosis, even in models of disease that have strong genetic determinants. It is well established that hyperlipidemia, inflammation and oxidative stress are the proximal vascular mechanisms in atherosclerosis, but the mediators linking social/emotional behavior to these drivers of disease are not clear. One of the most likely mediators linking social environment to disease is the sympathetic nervous system (SNS), and in preliminary work, we have observed that there is SNS hyperinnervation in atherosclerotic vascular tissue. This chronic SNS structural plasticity is proposed to exacerbate vascular inflammation, oxidative stress, and the progression of atherosclerosis. The proposed work will examine whether this SNS remodeling occurs in response to social environment or to the presence of local disease. We will also assess whether preventing this SNS hyperinnervation attenuates vascular inflammation and the progression of atherosclerosis. Therefore, the specific aims of the project are: 1a.) to examine SNS innervation density of vascular tissue in WHHLs vs normolipidemic control rabbits (New Zealand White; NZW) over time as a function of social environment, and to relate these differences to the progression of atherosclerosis, 1b.) to examine SNS innervation density of other peripheral tissue in WHHLs vs NZWs as a function of social environment, and 2.) to quantify vascular SNS innervation density, inflammation and atherosclerosis in WHHLs following pharmacological antagonism of NGF's target receptor, TrkA. The proposed research represents a novel approach to understanding how known risk factors (e.g., hyperlipidemia) may interact with behavioral variables to lead to the exacerbation or attenuation of disease. This type of SNS neuronal plasticity, and the resulting enhanced vascular inflammation/oxidative stress, may represent intervention targets for behavioral and/or pharmacological therapy in cardiovascular disease.

描述（由申请人提供）：拟议的研究将研究社会/情绪因素在动脉粥样硬化中的作用，并试图在生物行为危险因素，分子介体和临床疾病进展之间建立机械联系。这将通过使用渡边可遗传的高脂兔（WHHL）来实现，这是一种以高脂血症和严重的动脉粥样硬化为特征的遗传动物模型。我们已经证明，社会环境深刻影响WHHL的疾病进程，使得与同窝窝型稳定关系的动物，而不是在不稳定的社会条件或社会隔离下的WHHL，显示动脉粥样硬化的进展显着下降。一个以激动性行为和情感压力为特征的不稳定的社会环境与严重的高级动脉粥样硬化病变的发展有关。这些发现表明，即使在具有强大遗传决定因素的疾病模型中，生物行为因素在动脉粥样硬化的进展中也很重要。众所周知，高脂血症，炎症和氧化应激是动脉粥样硬化的近端血管机制，但是将社交/情感行为与这些疾病驱动因素联系起来的介体尚不清楚。将社会环境与疾病联系起来的最有可能的调解人之一是交感神经系统（SNS），在初步工作中，我们观察到动脉粥样硬化血管组织中有SNS过度连接。提出这种慢性SNS结构可塑性会加剧血管炎症，氧化应激和动脉粥样硬化的进展。拟议的工作将检查这种SNS重塑是响应社会环境还是当地疾病的存在。我们还将评估防止这种SNS过度作用会减轻血管炎症和动脉粥样硬化的进展。 Therefore, the specific aims of the project are: 1a.) to examine SNS innervation density of vascular tissue in WHHLs vs normolipidemic control rabbits (New Zealand White; NZW) over time as a function of social environment, and to relate these differences to the progression of atherosclerosis, 1b.) to examine SNS innervation density of other peripheral tissue in WHHLs vs NZWs as a社交环境的功能和2。）在NGF的靶受体TRKA的药理学拮抗作用后，WHLS中量化血管SN的神经神经密度，炎症和动脉粥样硬化。拟议的研究代表了一种新的方法，可以理解已知危险因素（例如高脂血症）如何与行为变量相互作用，从而导致疾病的加剧或衰减。这种类型的SNS神经元可塑性以及所得的增强的血管炎症/氧化应激，可能代表了心血管疾病中行为和/或药理治疗的干预靶标。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Oxytocin reduces adipose tissue inflammation in obese mice.

催产素可减少肥胖小鼠的脂肪组织炎症。

DOI：
10.1186/s12944-020-01364-x
发表时间：
2020
期刊：
Lipids in health and disease
影响因子：
4.5
作者：
Szeto,Angela;Cecati,Monia;Ahmed,Raisa;McCabe,PhilipM;Mendez,ArmandoJ
通讯作者：
Mendez,ArmandoJ

A Practical Approach to Quantitative Processing and Analysis of Small Biological Structures by Fluorescent Imaging.

DOI：
10.7171/jbt.16-2703-001
发表时间：
2016-09-01
期刊：
Journal of biomolecular techniques : JBT
影响因子：
0
作者：
Noller, Crystal M;Boulina, Maria;Mendez, Armando J
通讯作者：
Mendez, Armando J

Structural Remodeling of Sympathetic Innervation in Atherosclerotic Blood Vessels: Role of Atherosclerotic Disease Progression and Chronic Social Stress.

动脉粥样硬化血管交感神经支配的结构重塑：动脉粥样硬化疾病进展和慢性社会压力的作用。

DOI：
10.1097/psy.0000000000000360
发表时间：
2017
期刊：
Psychosomatic medicine
影响因子：
3.3
作者：
Noller,CrystalM;Mendez,ArmandoJ;Szeto,Angela;Boulina,Marcia;Llabre,MariaM;Zaias,Julia;Schneiderman,Neil;McCabe,PhilipM
通讯作者：
McCabe,PhilipM