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）：淋巴流动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，运输淋巴管被认为是组织引流管，最多只能推动淋巴液。然而，肠系膜淋巴管（MLV）位于肠腔的生物侵袭性环境和腹部内室之间的边界，这些淋巴管从未被视为抗炎防御的活性成分而被深入考虑和研究。肠系膜系统。通过内皮源性释放一氧化氮和组胺来改变其收缩性，MLV 可能会影响发炎和/或污染的淋巴成分下游扩散的速度，具体取决于病原体的性质和炎症反应的程度/阶段。与此同时，MLV 可能会影响其附近发育良好的肥大细胞群。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邻近MLV的收缩性，进一步调整MLV的功能以响应肠道和肠系膜炎症和水肿期间改变的淋巴内条件。该项目的中心假设是，肠系膜淋巴管和靠近它们的肥大细胞作为一个双向生物系统发挥作用，其中两个组成部分相互影响，并根据情况调整其功能活动水平。炎症相关的淋巴液含量变化的性质。为了检验中心假设，拟议的研究将侧重于以下特定目标。目的 1. 确定代表发炎/污染淋巴成分（炎症介质、微生物结构成分、抗原）的受控淋巴内应用物质对肠系膜淋巴管收缩性和位于其附近的肥大细胞活化的影响。目标 2. 确定肠系膜淋巴管壁衍生分子在出现发炎/污染的淋巴液后对淋巴管附近肥大细胞激活的相对作用。目标 3. 阐明肥大细胞衍生分子在发炎/污染淋巴诱导肥大细胞激活后调节肠系膜淋巴管收缩性中的作用。拟议研究的创新方法将包括在受控的淋巴内压力和流量、免疫组织化学和活体染料成像、药理学阻断和基因修饰下对邻近组织中的淋巴管和细胞成分的功能状态进行综合评估。拟议的研究不仅将为炎症和组织水肿发展过程中 MLV-组织相互作用的机制提供新颖的多层次理解，而且将为更精确地识别 MLV 病理干扰成分的治疗靶点提供独特的基础。 “淋巴管-组织”系统。