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/情感因素在动脉粥样硬化中的作用，并试图建立生物行为危险因素、分子介质和临床疾病进展之间的机制联系。这将通过使用渡边遗传性高脂血症兔（WHHL）来实现，这是一种以高脂血症和严重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 的病程，因此与同窝动物关系稳定的动物，与社会条件不稳定或社会隔离的 WHHL 不同，动脉粥样硬化的进展显着减少。以竞争行为和情绪压力为特征的不稳定的社会环境与严重、晚期动脉粥样硬化病变的发展有关。这些发现表明，生物行为因素在动脉粥样硬化的进展中很重要，即使在具有强遗传决定因素的疾病模型中也是如此。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，但将社会/情绪行为与这些疾病驱动因素联系起来的中介因素尚不清楚。将社会环境与疾病联系起来的最可能的介质之一是交感神经系统（SNS），在前期工作中，我们观察到动脉粥样硬化血管组织中存在SNS过度神经支配。这种慢性 SNS 结构可塑性被认为会加剧血管炎症、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 重塑是否是对社会环境或当地疾病的存在做出反应而发生的。我们还将评估防止这种 SNS 过度神经支配是否可以减轻血管炎症和动脉粥样硬化的进展。因此，该项目的具体目标是： 1a.) 检查 WHHL 与血脂正常对照兔子（新西兰白兔；NZW）的血管组织 SNS 神经支配密度随时间的变化作为社会环境的函数，并将这些差异与动脉粥样硬化的进展，1b.) 检查 WHHL 与 NZW 中其他外周组织的 SNS 神经支配密度作为社会环境的函数，以及 2.) 量化NGF 靶受体 TrkA 药理拮抗后 WHHL 中血管 SNS 神经支配密度、炎症和动脉粥样硬化。拟议的研究代表了一种新的方法来了解已知的危险因素（例如高脂血症）如何与行为变量相互作用，从而导致疾病的恶化或减弱。这种类型的 SNS 神经元可塑性以及由此产生的血管炎症/氧化应激增强可能代表心血管疾病行为和/或药物治疗的干预目标。

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：
发表时间：
2020-08-20
期刊：
影响因子：
0
作者：
Szeto, Angela;Cecati, Monia;Ahmed, Raisa;McCabe, Philip M;Mendez, Armando J
通讯作者：
Mendez, Armando J

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

通过荧光成像定量处理和分析小型生物结构的实用方法。

DOI：
发表时间：
2016-09
期刊：
影响因子：
0
作者：
Noller, Crystal M;Boulina, Maria;McNamara, George;Szeto, Angela;McCabe, Philip M;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：
发表时间：
2017-01
期刊：
影响因子：
3.3
作者：
Noller, Crystal M;Mendez, Armando J;Szeto, Angela;Boulina, Marcia;Llabre, Maria M;Zaias, Julia;Schneiderman, Neil;McCabe, Philip M
通讯作者：
McCabe, Philip M