Role of Lymphatic Clearance in Lipid-Induced Calcific Vasculopathy and Bone Loss

淋巴清除在脂质引起的钙化性血管病和骨丢失中的作用

基本信息

批准号：
8308373
负责人：
Linda L. Demer
金额：
$ 23.1万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8308373
关键词：
Aerobic Agitation American Antioxidants Area Arteries Atherosclerosis Behavior Blood Blood Circulation Blood capillaries Bone Diseases Breathing Cardiovascular Diseases Cardiovascular system Chronic Clinical Complement Deposition Diet Disease Duct (organ) structure Epitopes Feeds Frequencies Heart Diseases Hyperlipidemia Immune In Vitro Inflammation Inflammatory Inflammatory Response Injury Intervention Lead Life Style Lipids Lipoproteins Liquid substance Liver Liver Circulation Lung Lymphatic Lymphatic Capillaries Lymphatic vessel Mechanical Stress Mechanics Modification Molecular Morbidity - disease rate Mus Muscle Contraction Myocardial Infarction Osteitis Osteoporosis Pathogenesis Physical activity Physiological Pilot Projects Prevention Production Pump Research Role Sedation procedure Series Signal Transduction Skeletal Muscle Sturnus vulgaris Testing Therapeutic Therapeutic Intervention Thoracic Duct Thoracic cavity structure Time Tissues Translating Vascular Diseases Vascular calcification Venous Work behavioral impairment bone bone loss capillary falls glycation improved in vivo interstitial lipoprotein cholesterol lymphatic circulation mortality mouse model novel oxidation oxidized lipid pressure prevent residence reverse cholesterol transport sedative sedentary vascular inflammation

项目摘要

DESCRIPTION (provided by applicant): Atherosclerosis remains a major cause of morbidity and mortality despite substantial therapeutic interventions. Evidence suggests that the ever-more sedentary lifestyle of Americans is undermining the benefits of lipid- lowering therapy. It is widely accepted that tissue deposition and modification of lipoproteins induce inflammation and atherosclerosis; we and others are now showing that the same mechanism underlies vascular calcification and bone loss. It is well known that the interstitial spaces of tissues are normally cleared by fluid circulation through the lymphatic circulatory system, and that lymphatic circulation, which has no pump, depends on physical activity. Interestingly, cardiovascular disease is reduced by even mild physical activity -- below levels that promote aerobic capacity -- through mechanisms that are not known. One promising area of atherosclerosis research is reverse cholesterol transport, which focuses on removing lipoprotein deposits from the interstitial spaces of the artery wall to the circulation for hepatic clearance. However, if sedentary behavior impairs lymphatic circulation, enhancing reverse cholesterol transport at the molecular level may not translate to clinical benefit. Integrative physiological approaches are needed to complement the current molecular approach to reverse cholesterol transport. We hypothesize that enhancing lymphatic clearance reduces stagnation of lipoproteins in the interstitial spaces and prevents vascular and bone inflammation and disease. To test this novel hypothesis, we will develop interventions to maximize and minimize lymphatic flow in a mouse model of atherosclerosis and osteoporosis. We will use three interventions to induce changes in lymphatic clearance in mice: 1) Lyve1 deficiency, which enhances baseline lymphatic circulation, 2) controlled physical activity, to increase lymphatic flow, and 3) sedatives to reduce lymphatic flow. In Specific Aim 1, we will explore the effects of maximal vs. minimal lymphatic clearance on vascular disease using diet-induced atherosclerosis and vascular calcification in hyperlipidemic mice. In Specific Aim 2, we will explore the effects of maximal vs. minimal lymphatic clearance on bone disease using diet-induced osteoporosis in hyperlipidemic mice. In this pilot study, we will explore the levels of frequency and intensity of activity required to induce lymphatic flow, and test whether maximizing lymphatic circulation prevents vascular and bone disease. Findings of this work could introduce a promising new direction of research and greatly benefit prevention and treatment of atherosclerosis and osteoporosis.

描述（由申请人提供）：尽管进行了大量治疗性干预，但动脉粥样硬化仍然是发病率和死亡率的主要原因。证据表明，美国人的久坐久坐生活方式正在破坏脂质降低疗法的好处。人们普遍认为，脂蛋白的组织沉积和修饰会诱导炎症和动脉粥样硬化。我们和其他人现在表明，相同的机制是血管钙化和骨质流失的基础。众所周知，组织的间隙空间通常通过淋巴循环系统的流体循环清除，没有泵的淋巴循环取决于体育活动。有趣的是，通过未知的机制，甚至通过轻度的体育活动（低于促进有氧能力的水平）减少了心血管疾病。动脉粥样硬化研究的一个有前途的区域是反向胆固醇转运，该胆固醇的转运重点是从动脉壁的间隙空间去除脂蛋白沉积物到循环以进行肝清除。但是，如果久坐的行为会损害淋巴循环，则在分子水平上增强反向胆固醇的转运可能不会转化为临床益处。需要进行综合的生理方法来补充当前的分子方法逆转胆固醇的转运。我们假设增强淋巴清除率会减少脂蛋白在间质空间中的停滞，并防止血管和骨骼炎症和疾病。为了检验这一新的假设，我们将开发干预措施，以最大程度地提高和最小化动脉粥样硬化和骨质疏松症小鼠模型中的淋巴流量。我们将使用三种干预措施诱导小鼠淋巴清除的变化：1）Lyve1缺乏症，增强了基线淋巴循环，2）受控的体育活动，以增加淋巴流动，3）镇静剂以减少淋巴流量。在特定的目标1中，我们将使用饮食诱导的动脉粥样硬化和高脂症小鼠的血管钙化对血管疾病的最大与最小淋巴清除率对血管疾病的影响。在特定的目标2中，我们将使用饮食诱导的高脂症小鼠探索最大与最小淋巴清除对骨骼疾病的影响。在这项试点研究中，我们将探索诱导淋巴流动所需的活动频率和强度水平，并测试最大化淋巴循环是否可以防止血管和骨骼疾病。这项工作的发现可能会引入一个有希望的新的研究方向，并极大地使预防和治疗动脉粥样硬化和骨质疏松症的治疗。