Mechanisms of the Age-related Alterations in Lymphatic Pumping

描述（由申请人提供）：淋巴系统的主要任务是淋巴转运。这个血管和淋巴结系统被设计成将液体、可溶性分子和细胞从淋巴结通过淋巴结输送到中央静脉。淋巴系统在体液循环、大分子体内平衡、脂肪吸收和免疫中起着重要作用。尽管所有这些身体系统都受到衰老的影响，但衰老对这些身体功能中任何一种淋巴转运成分的影响尚不清楚。特别是，很少有人知道与年龄有关的变化的阶段性收缩的淋巴管，这是至关重要的淋巴液流动的产生。当它们的收缩性通过压力和流量依赖性调节机制不断地调节局部流体负荷时，运输流体以“自我调节模式”工作。这个建议的中心假设是，老化调制的压力和流量依赖性的调节机制，在philatics。这将导致淋巴收缩性的功能性适应性储备的退化，这是由于eNOS/iNOS的不平衡沿着钙敏感性的改变和淋巴细胞中的横桥激活机制。这种与年龄相关的淋巴转运系统的变化可能会降低淋巴细胞为许多身体功能提供足够淋巴转运组分的能力。具体目标是：1）确定淋巴管对跨壁压的敏感性的年龄相关变化，并评估其适应性收缩储备，2）确定淋巴管的主动机械性质的年龄相关变化，3）确定原位流动/壁剪切应力分布的年龄相关变化，以及它们对分离的淋巴管中的施加流动的敏感性，4）探讨淋巴管收缩力增龄性改变的分子机制，建立改善老年人淋巴管收缩力下降的实验模型。所有拟定研究均将使用9和24月龄大鼠的肠系膜血管和胸导管（Fischer-344 NIA）。我们预计，在收缩和调节蛋白成分和/或内皮细胞功能障碍的变化是受损的压力/流量诱导的功能反应的老年人的基础。本研究的结果将提供不同组织中与年龄相关的过程之间的缺失环节，以及老年生物体中淋巴细胞提供淋巴液充分转运能力的与年龄相关的差异变化。该提案的数据还将为改善衰老过程中受损的淋巴转运的方法提供基础知识。 叙述：这些研究将提供关于衰老如何改变老年人淋巴泵的重要新信息。所提出的实验模型的开发，以及在这些研究中获得的新的科学知识，将为未来治疗老年人群中常见的水肿（损害不同组织的功能）的治疗方法的开发提供科学依据。

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.