Quantifying the role of load-induced remodeling in lymphedema progression

量化负荷诱导的重塑在淋巴水肿进展中的作用

基本信息

批准号：
8505748
负责人：
James Brandon Dixon
金额：
$ 46.78万
依托单位：
GEORGIA INSTITUTE OF TECHNOLOGY
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：
2013-08-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8505748
关键词：
Adverse effects Affect Animal Model Anxiety Area Arteries Atherosclerosis Biomechanics Biomedical Engineering Blood Vessels Cancer Survivor Cell Proliferation Cells Clinical Collagen Computer Simulation DNA Sequence Rearrangement Deposition Dermal Deterioration Developed Countries Disease Disease Progression Disease susceptibility Drainage procedure Early Diagnosis Engineering Environment Extracellular Matrix Fatigue Functional disorder Goals Growth Health Care Costs Image Immune In Vitro Incidence Infection Intervention Left Life Life Expectancy Limb structure Lipids Liquid substance Lymphatic Lymphatic Diseases Lymphatic System Lymphatic vessel Lymphedema Massage Mastectomy Measures Mechanics Mental Depression Methods Microscopy Modeling Morbid Obesity Nature Neoplasm Metastasis Outcome Pathology Pathway interactions Patients Persons Play Prevalence Process Proteins Rattus Reporting Research Risk Role Severities Severity of illness Skin Care Staging Stimulus Stress Structure-Activity Relationship System Tail Technology Testing Tissue Engineering Tissues Work animal tissue base burden of illness chronic pain functional decline in vivo Model innovation insight lipid transport lymphatic pump malignant breast neoplasm mimetics novel novel strategies pressure prevent public health relevance response trafficking

项目摘要

DESCRIPTION (provided by applicant): Recent estimates suggest that the prevalence of lymphedema in developed countries is as high as 1.44 per thousand persons. Consequences of the disease include an increase in chronic pain and fatigue, higher incidence of dermal infections, severe anxiety and depression, a 10 year decrease in life expectancy with doubled health care costs. Yet in spite of the growing burden of this disease, clinical options available fr most suffering patients are the same today as 30 years ago: namely proper skin care and various methods of tissue compression. Such approaches have the goal of reducing symptomatic severity, while failing to understand or correct the underlying dysfunction. Lymphatic function is highly sensitive to the forces imposed on the vessels, and lymphedema drastically alters the local mechanical environment of the interstitium surrounding lymphatics through substantial collagen and lipid accumulation. A comprehensive understanding of the crosstalk between this environment and lymphatic function, particularly in the context of lymphedema, would therefore have significant clinical benefits not only for patients suffering from lymphedema, but also for patients with other diseases where lymphatics have been implicated, such as impaired immune cell trafficking, severe obesity, atherosclerosis, and cancer metastasis. The objective of this project is to develop a predictive framework that quantitatively describes the interplay between mechanical loading, lymphatic growth and remodeling, and lymphatic function by using experimental approaches at the animal, tissue and cellular levels. Our central hypothesis is that sustained abnormally elevated mechanical loading on a collecting lymphatic vessel induces a remodeling response by the vessel, which promotes cell proliferation and increased matrix deposition until it reaches a threshold at which this response negatively affects lymphatic transport, altering the tissue microenvironment and further compromising fluid, protein, and lipid transport by the lymphatic system. This hypothesis will be tested through two Specific Aims: 1) Quantify the growth and remodeling response of the lymphatic microstructure to sustained mechanical loading; and 2) Quantify the effects of this growth and remodeling response on lymphatic function and vessel mechanics. The rationale for this work is that it will provide mechanistic insight into the progression of lymphedema, identifying pathways for intervention that will restore lymphatic function. We anticipate that the findings from these studies will have an impact on the treatment of lymphatic disease by paving the way for patient specific modeling and for prediction of lymphedema risk through the use of integrated lymphatic imaging and computational modeling toolsets.

描述（由申请人提供）：最近的估计表明，发达国家淋巴水肿的患病率高达每千人1.44。疾病的后果包括增加慢性疼痛和疲劳，皮肤感染的发病率更高，严重的焦虑和抑郁症，预期寿命降低了10年，医疗保健成本增加了一倍。然而，尽管这种疾病的负担越来越大，但可提供的临床选择fr今天与30年前的患者相同：即适当的皮肤护理和各种组织压缩方法。这种方法的目的是减少症状严重程度，同时无法理解或纠正潜在的功能障碍。淋巴功能对施加在血管上的力高度敏感，淋巴水肿通过大量的胶原蛋白和脂质积累大大改变了周围淋巴周围遗迹的局部机械环境。因此，对这种环境与淋巴功能之间的串扰的全面了解，尤其是在淋巴水肿的背景下，不仅对患有淋巴水肿的患者，而且对于患有淋巴细胞的其他疾病的患者，也将具有显着的临床益处，例如涉及淋巴问题的其他疾病，例如免疫细胞运输，严重的肥胖，严重肥胖，抗衰老和癌变。该项目的目的是开发一个预测框架，该框架通过使用动物，组织和细胞水平的实验方法来定量地描述机械负荷，淋巴生长和重塑与淋巴功能之间的相互作用。 Our central hypothesis is that sustained abnormally elevated mechanical loading on a collecting lymphatic vessel induces a remodeling response by the vessel, which promotes cell proliferation and increased matrix deposition until it reaches a threshold at which this response negatively affects lymphatic transport, altering the tissue microenvironment and further compromising fluid, protein, and lipid transport by the lymphatic system.该假设将通过两个具体目的进行检验：1）量化淋巴微结构对持续机械负荷的生长和重塑反应； 2）量化这种生长和重塑反应对淋巴功能和血管力学的影响。这项工作的理由是，它将提供对淋巴水肿进展的机械洞察力，从而确定将恢复淋巴功能的干预途径。我们预计，这些研究的发现将通过使用综合淋巴成像和计算建模工具集为患者特定的建模和预测淋巴水肿风险的方式来影响淋巴病的治疗。