Bidirectional Regulatory Interactions Between Lymph Vessel and Adjacent Tissues

淋巴管与邻近组织之间的双向调节相互作用

基本信息

批准号：
8919518
负责人：
ANATOLIY A GASHEV
金额：
$ 21.83万
依托单位：
TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-15 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8919518
关键词：
Abdomen Adsorption Anti-Inflammatory Agents Anti-inflammatory Antigens Appearance Area Biological Biology Body Fluids Cell physiology Cells Data Development Dyes Edema Elements Endothelium Environment Evaluation Genetic Health Histamine Homeostasis Human Image Immune Indium Inflammation Inflammation Mediators Inflammatory Inflammatory Response Laboratories Lipids Liquid substance Lymph Lymphatic Lymphatic vessel Maintenance Mammals Mesentery Modification Muscle Contraction Nature Nitric Oxide Pattern Population Positioning Attribute Reaction Regulation Relative (related person)Research Role Scheme Staging Structure Surface System Technology Testing Time Tissues Transportation Tube Veins absorption base biological systems functional status innovation lymph flow lymph nodes mast cell microbial novel pathogen pressure response therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Lymph flow is necessary for fluid and macromolecular homeostasis as well as transportation of lipids and immune cells. Historically, the transporting lymphatic vessels were considered as tissue-draining tubes, which at best were able to propel lymph. However, mesenteric lymphatic vessels (MLVs) being located at the border between the biologically aggressive environment of the gut lumen and inner compartments of the abdomen, these lymph vessels have never been considered and studied in depth as an active component of the anti- inflammatory defense system of the mesentery. By changing their contractility through endothelium-derived release of nitric oxide and histamine, MLVs may influence the rapidity of downstream spread of the components of inflamed and/or contaminated lymph, depending on the nature of the pathogen and the degree/stage of the inflammatory response. At the same time, MLVs may influence a well-developed population of mast cells located nearby them. Mast cells may stimulate or inhibit the contractility of adjacent MLVs through the release of a combination of several biologically active substances, further adapting the function of MLVs in response to altered intralymphatic conditions during gut and mesenteric inflammation and edema. The central hypothesis of the proposed project is that mesenteric lymphatic vessels and mast cells located in close proximity to them are functioning as a bi-directional biological system, in which both components are influencing each other and adapting the levels of their functional activity depending on the nature of the inflammation-related changes in lymph content. To test the central hypothesis the proposed studies will focus on following specific aims. Aim 1. To determine the effects of controlled intralymphatic application of substances representing elements of inflamed/contaminated lymph (inflammatory mediators, components of microbial structures, antigen) on contractility of mesenteric lymphatic vessels and on activation of mast cells located near them. Aim 2. To determine the relative roles of mesenteric lymphatic wall-derived molecules on activation of mast cells located near lymphatics subsequent to appearance of the inflamed/contaminated lymph. Aim 3. To elucidate the roles of mast cell-derived molecules in regulation of the contractility of mesenteric lymphatic vessels after mast cell activation induced by inflamed/contaminated lymph. The innovative approach of the proposed research will include combined evaluations of the functional status of lymphatic vessels and cellular elements in adjacent tissues under controlled intralymphatic pressure and flow, immunohistochemical and vital dye imaging, pharmacological blockade and genetic modifications. The proposed research will not only provide novel multi-level understanding of the mechanisms involved in MLV-tissue interactions during the development of inflammation and tissue edema, but will offer a unique basis for more precise identification of therapeutic targets of the pathologically disturbed components of the "lymphatic vessel-tissue" system.

描述（由申请人提供）：淋巴流量对于液体和大分子稳态以及脂质和免疫细胞的运输是必需的。从历史上看，转运淋巴管被认为是组织排水管，充其量是能够推动淋巴的。然而，肠道淋巴管（MLV）位于肠道内腔的生物侵略性环境与腹部内部区室之间的边界，从未考虑过这些淋巴管，并将这些淋巴血管深入研究，并作为肠内炎性防御系统的活跃成分进行了深入研究。通过通过内皮衍生的一氧化氮和组胺的释放来改变其收缩力，MLV可能会影响发炎和/或受污染淋巴的下游分量的快速扩散，这取决于病原体的性质以及炎症反应的程度/阶段。同时，MLV可能会影响附近的肥大细胞的发达的人群。肥大细胞可以通过释放几种生物活性物质的组合来刺激或抑制相邻MLV的收缩力，从而进一步适应MLV的功能，以响应于肠内炎症和肠系膜炎症和水肿过程中的内膜内条件的改变。拟议项目的核心假设是，肠系膜淋巴管和肥大细胞与它们近距离接近，是双向生物学系统的作用，其中两个成分互相影响，并根据淋巴含量的炎症性质变化的性质来适应其功能活性的水平。为了检验中心假设，拟议的研究将集中于以下特定目标。目的1。确定受控内膜片的施用的影响，代表发炎/污染的淋巴元素（炎症介质，微生物结构的成分，抗原）对肠系膜淋巴管的收缩性以及附近肥大细胞的激活。目的2。确定肠系膜淋巴壁源分子在发炎/污染淋巴外出现后位于淋巴管附近的肥大细胞激活的相对作用。目的3。阐明肥大细胞衍生的分子在肥大/污染淋巴引起的肥大细胞激活后调节肠系膜淋巴管的收缩力的作用。拟议的研究的创新方法将包括对受控内膜压力和流动，免疫组织化学和有生命的染料成像，药理阻滞和遗传修饰的淋巴管和细胞元素的功能状态的结合评估。拟议的研究不仅将提供对炎症和组织水肿发展中涉及的MLV组织相互作用机制的新型多层次理解，而且还将为更精确地识别“淋巴管 - 触摸系统”系统的病理干扰成分的治疗靶标提供独特的基础。