Quantifying the role of load-induced remodeling in lymphedema progression

描述（由申请人提供）：最近的估计表明，发达国家的水肿患病率高达每千人1.44例。这种疾病的后果包括慢性疼痛和疲劳增加，皮肤感染发病率增加，严重焦虑和抑郁，预期寿命减少10年，医疗保健费用增加一倍。然而，尽管这种疾病的负担越来越重，但今天大多数患者的临床选择与30年前相同：即适当的皮肤护理和各种组织压迫方法。这些方法的目标是降低症状的严重程度，而不能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，并且水肿通过大量胶原蛋白和脂质积累而急剧改变了血管周围的淋巴结的局部机械环境。因此，对这种环境与淋巴功能之间的串扰的全面理解，特别是在水肿的背景下，不仅对患有水肿的患者，而且对患有涉及淋巴功能的其他疾病的患者，如受损的免疫细胞运输、严重肥胖、动脉粥样硬化和癌症转移，都具有显著的临床益处。该项目的目标是开发一个预测框架，通过在动物，组织和细胞水平上使用实验方法定量描述机械负荷，淋巴生长和重塑以及淋巴功能之间的相互作用。我们的中心假设是，集合淋巴管上持续异常升高的机械负荷诱导血管的重塑反应，这促进细胞增殖并增加基质沉积，直到达到阈值，在该阈值下，这种反应对淋巴转运产生负面影响，改变组织微环境并进一步损害淋巴系统的液体、蛋白质和脂质转运。该假设将通过两个特定目的进行检验：1）量化淋巴微结构对持续机械负荷的生长和重塑反应; 2）量化该生长和重塑反应对淋巴功能和血管力学的影响。这项工作的基本原理是，它将提供对水肿进展的机制性见解，确定恢复淋巴功能的干预途径。我们预计，这些研究的结果将对淋巴疾病的治疗产生影响，为患者特异性建模铺平道路，并通过使用集成的淋巴成像和计算建模工具集预测水肿风险。

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.