Mechanisms of the Age-related Alterations in Lymphatic Pumping

描述(申请人提供)：淋巴系统的主要任务是淋巴运输。这种血管和结节系统的设计是为了将液体、可溶性分子和细胞从间质通过淋巴结输送到中央静脉。淋巴系统在体液循环、大分子动态平衡、脂肪吸收和免疫等方面起着重要作用。尽管所有这些身体系统都会受到衰老的影响，但衰老对其中任何一种身体功能的淋巴运输成分的影响尚不清楚。特别是，对淋巴管的时相收缩与年龄相关的改变知之甚少，这对淋巴流的产生至关重要。当淋巴管的收缩能力通过依赖于压力和流量的调节机制不断调整以适应局部流体负荷时，淋巴管的运输以“自我调节模式”工作。这一建议的中心假设是，衰老调节淋巴管中依赖压力和流量的调节机制。这将导致淋巴收缩功能适应性储备的退化，这是由于eNOS/iNOS失衡以及淋巴管钙敏感性和交叉桥激活机制的改变。这种与年龄相关的淋巴运输系统的变化可能会削弱淋巴管为许多身体功能提供足够的淋巴运输成分的能力。其具体目的是：1)确定淋巴管对跨壁压力的敏感性的年龄相关变化，并评估其适应性收缩储备；2)确定淋巴管主动机械性能的年龄相关变化；3)原位确定流动/壁切应力分布的年龄相关变化及其对分离淋巴管中外加流量的敏感性；4)研究与年龄相关的淋巴管收缩能力改变的分子机制，并建立改善老年淋巴管淋巴收缩能力减弱的实验模型。所有拟议的研究将使用9个月和24个月大鼠(Fischer-344 NIA)的肠系膜淋巴管和胸管。我们预测，收缩和调节蛋白成分的变化和/或内皮细胞功能障碍是老年淋巴管压力/流量诱导的功能反应受损的基础。这项研究的结果将提供不同组织中与年龄相关的过程与老年生物中淋巴管提供足够的淋巴运输能力的年龄相关差异变化之间的缺失联系。这项提案的数据还将为改善淋巴运输的方法提供基本知识，淋巴运输在衰老过程中受到损害。 叙述：这些研究将为衰老如何改变老年人的淋巴泵提供重要的新信息。拟议的实验模型的发展，加上在这些研究中获得的新的科学知识，将为未来治疗老年人常见的、损害不同组织功能的浮肿的治疗方法的开发提供科学基础。

DESCRIPTION (provided by applicant): The major task of the lymphatic system is lymph transport. This system of vessels and nodes is designed to transport fluid, soluble molecules and cells from the interstitium through the lymph nodes to the central veins. The lymphatic system plays important roles in body fluid circulation, macromolecular homeostasis, fat absorption, and immunity. Although all of these body systems are affected by aging, the effects of aging on the lymphatic transport component of any of these body functions are unknown. Particularly, very little is known about the age-related alterations of phasic contractions of the lymphatics, which are critical to the generation of lymph flow. Transporting lymphatics work in a "self-regulatory mode" when their contractility constantly adjusts to the local fluid loads through pressure and flow dependent regulatory mechanisms. The central hypothesis of this proposal is that aging modulates the pressure and flow-dependent regulatory mechanisms in lymphatics. This will result in a regression of the functional adaptive reserves in lymphatic contractility due to the eNOS/iNOS disbalances along with alterations in calcium sensitivity and crossbridge activation mechanisms in lymphatics. Such age-related changes in lymph transport system could diminish the ability of lymphatics to provide adequate lymph transport component for many body functions. The specific aims are: 1) To determine the age-related changes in the sensitivity of lymphatic vessels to transmural pressure and to evaluate their adaptive contractile reserves, 2) To determine the age-related changes in the active mechanical properties of the lymphatic vessels, 3) To determine the age-related changes in flow/walls shear stress profiles in situ and in their sensitivity to imposed flow in isolated lymphatic vessels, 4) To investigate the molecular mechanisms responsible for age-related alterations of lymphatic contractility and to develop an experimental model to improve the diminished lymphatic contractility in aged lymphatics. Mesenteric lymphatics and thoracic duct from 9 and 24 mo rats (Fischer-344 NIA) will be used for all proposed studies. We anticipate that changes in the contractile and regulatory protein components and/or endothelium cell dysfunction are the basis for the impaired pressure/flow-induced functional responses of the aged lymphatics. The results of this research will provide the missing link between the age- related processes in the different tissues and the age-related differential changes in the ability of lymphatics to provide the adequate transport of lymph from them in elderly organisms. Data from this proposal will also provide the basic knowledge for the ways to improve lymphatic transport that is compromised during aging. Narrative: These studies will provide important new information on how aging alters lymphatic pumping in the elderly. The development of the proposed experimental model, together with novel scientific knowledge obtained in these studies, will provide a scientific basis for the development of future therapies to treat the edema that commonly occurs in the elderly population, impairing the functioning of different tissues.