Mechanisms of the Age-related Alterations in Lymphatic Pumping

淋巴泵随年龄变化的机制

• 批准号: 7460037
• 负责人: ANATOLIY A GASHEV
• 金额: $ 30.11万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-15 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7460037
• 关键词: Acute; Adrenergic Agonists; Adult; Affect; Age; Aging; Aging-Related Process; Animals; Beds; Biology; Blood Circulation; Blood Plasma Volume; Blood capillaries; Body Fluids; Body Regions; Ca(2+)-Transporting ATPase; Calcium; Caliber; Cells; Central Vein; Characteristics; Clinical; Computers; Condition; Contracts; Data; Development; Disease regression; Edema; Effectiveness; Elderly; Endoplasmic Reticulum; Endothelial Cells; Endothelium; Experimental Models; Fatty acid glycerol esters; Fluorescence Microscopy; Freezing; Functional disorder; Future; Generations; Genes; Goals; Green Fluorescent Proteins; Heterogeneity; Homeostasis; Human; Image; Immunity; In Situ; Inbred F344 Rats; Inflammatory; Injury; Intercellular Fluid; Isometric Exercise; Isotonic Exercise; Knowledge; Length; Life; Link; Liquid substance; Lymph; Lymphatic; Lymphatic System; Lymphatic vessel; Lymphocyte; Lymphoid Tissue; MYLK gene; Measurement; Measures; Mechanics; Mediating; Mediator of activation protein; Mesentery; Microfilaments; Modeling; Molecular; Monitor; Muscle; Muscle Cells; Nature; Nitrogen; Organism; Output; Pathway interactions; Pattern; Physiological; Play; Population; Preparation; Property; Protein Overexpression; Proteins; Protocols documentation; Pump; RNA; Range; Rate; Rattus; Reaction; Regulation; Relative (related person); Research; Resistance; Role; Route; Skin; Smooth Muscle; Speed; Stretching; Study Section; Substance P; System; Techniques; Testing; Thin Filament; Thoracic Duct; Tissues; Transfection; Transportation; Tropomyosin; Velocimetries; Western Blotting; Work; absorption; age effect; age related; aged; base; body system; caldesmon; capillary; day; design; genetic regulatory protein; improved; innovation; insight; interest; lymph flow; lymph nodes; mRNA Expression; macromolecule; neoplastic cell; novel; particle; pressure; research and development; research study; response; shear stress; tool

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.

描述（由申请人提供）： 淋巴系统的主要任务是淋巴液运输。这个血管和节点系统旨在将液体、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、大分子稳态、脂肪吸收、免疫等方面发挥着重要作用。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的淋巴运输部分的影响尚不清楚。特别是，人们对淋巴管阶段性收缩与年龄相关的变化知之甚少，而淋巴管阶段性收缩对于淋巴液流的产生至关重要。当淋巴管的收缩力通过压力和流量依赖的调节机制不断调整以适应局部液体负荷时，输送淋巴管以“自我调节模式”工作。该提议的中心假设是衰老调节淋巴管中的压力和流量依赖性调节机制。由于 eNOS/iNOS 失衡以及淋巴管中钙敏感性和跨桥激活机制的改变，这将导致淋巴收缩力的功能适应性储备退化。淋巴运输系统的这种与年龄相关的变化可能会降低淋巴管为许多身体功能提供足够的淋巴运输成分的能力。具体目标是： 1) 确定淋巴管对跨壁压力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特性的年龄相关变化，3) 确定原位流动/壁剪切应力分布及其对孤立淋巴管中强加流动的敏感性的年龄相关变化，4) 研究与年龄相关的淋巴收缩力改变的分子机制，并开发一个实验模型来改善老年淋巴管中淋巴收缩力的减弱。 9 个月和 24 个月大鼠 (Fischer-344 NIA) 的肠系膜淋巴管和胸导管将用于所有拟议的研究。我们预计收缩和调节蛋白成分的变化和/或内皮细胞功能障碍是老化淋巴管压力/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之间缺失的联系，以及老年生物体中淋巴管提供足够的淋巴液运输能力的与年龄相关的差异变化。该提案的数据还将提供改善衰老过程中受损的淋巴运输的方法的基础知识。 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。所提出的实验模型的开发，加上这些研究中获得的新科学知识，将为未来治疗老年人群中常见的水肿（损害不同组织功能）的疗法的开发提供科学基础。