Modulation of Lymphatic System Function by LTB4

LTB4 对淋巴系统功能的调节

• 批准号: 9760778
• 负责人: Matthew Cribb
• 金额: $ 4.5万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-22 至 2021-07-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9760778
• 关键词: Academia; Acute; Affect; Arachidonic Acids; Arthritis; Asthma; Atherosclerosis; Automobile Driving; Breast Cancer Patient; Breast Cancer Treatment; Cauterize; Cells; Chemotactic Factors; Clinical; Clinical Trials; Deterioration; Development; Disease; Disease Progression; Dose; Drug Targeting; Exhibits; Exposure to; Failure; Fibrosis; Fluid Balance; Genetic; Histologic; Human; Hyperplasia; Imaging Techniques; Immune; Immune response; Impairment; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Injury; Institutes; Insulin Resistance; Intercellular Fluid; Knockout Mice; Knowledge; LTB4R gene; Left; Leukocytes; Leukotriene Antagonists; Leukotriene B4; Ligation; Limb structure; Lymphangiogenesis; Lymphatic; Lymphatic System; Lymphatic vessel; Lymphedema; Macrophage Activation; Measures; Mediating; Metabolism; Modeling; Mus; Natural regeneration; Near-infrared optical imaging; Nitric Oxide; Obese Mice; Operative Surgical Procedures; Pharmacological Treatment; Phenotype; Physiological; Play; Production; Property; Pump; Research; Research Institute; Research Personnel; Research Training; Resolution; Resources; Role; Site; Structure; Surgical Models; Swelling; System; Tail; Technology; Testing; Therapeutic; Tissues; Ubenimex; VEGFC gene; Work; career; improved; in vivo; lipid mediator; lymphatic pump; macrophage; mouse model; novel; receptor; recruit; response; small molecule inhibitor; wound

Project Abstract Lymphedema is a devastating disease that predominantly affects breast cancer patients post-surgery, leading to swelling at the extremities, tissue fibrosis, and general discomfort. There are currently no pharmacological treatments available for lymphedema. However, LTB4, a metabolite of arachidonic acid, has been implicated in the development of lymphedema and identified as a possible drug target. The objective of this study is to determine if LTB4 drives lymphatic collecting vessel failure and identify the direct mechanism of action for LTB4 on lymphatic collecting vessels. The hypothesis is that LTB4 inhibits lymphatic collecting vessel contraction at high concentrations occurring post-injury, leading to lymphatic insufficiency and the extreme swelling found in lymphedema. We predict that this functional effect of LTB4 occurs through two mechanisms; LTB4 directly acts on lymphatic collecting vessels to inhibit pumping, and LTB4 drives macrophage recruitment to the site of injury, further amplifying disease progression through secretion of VEGFC and iNOS, known effectors of lymphatic function. To test how LTB4 concentration affects lymphatic collecting vessel function, we will first use an isolated vessel setup to test the direct effect of varying concentrations of LTB4 on lymphatic vessel tone and contractility. We will also determine if the effect of LTB4 on lymphatic vessel contractility is mediated by its receptors, BLT1 and/or BLT2. Next, an LTB4 antagonist called bestatin will be used in conjunction with a single vessel ligation lymphedema model in mice to study how LTB4 affects collecting vessel function during disease progression. In the single vessel ligation model, the dominant collecting vessel and the surrounding initial lymphatics will be cauterized while one collecting vessel will be left intact. By using NIR imaging techniques to measure contractile function in this collecting vessel after surgery, the effect of LTB4 antagonism on contractile function during disease progression can be determined. This surgical model will be tested in a genetic macrophage depletion mouse model to examine if there is a macrophage-mediated effect of LTB4 on collecting vessel pump function during lymphedema development. VEGFC secretion and iNOS expression by macrophages will be quantified in the context of LTB4 antagonism to determine the mechanism by which macrophages modulate lymphatic function. The results of this study will help elucidate the role of LTB4 in the development of lymphedema, characterize its direct effect on lymphatic system function, and identify multiple mechanisms by which LTB4 drives lymphatic collecting vessel pump failure. These results will be an important step towards a better understanding of lymphedema progression and will inform the use of pharmacotherapeutic treatments for lymphedema targeting LTB4 and its metabolism. The research training will take place at the Georgia Institute of Technology, a world-class research institute with ample facilities and resources to help guide a young researcher towards a career in academia.

项目摘要 淋巴水肿是一种毁灭性的疾病，主要影响手术后的乳腺癌患者， 导致四肢肿胀、组织纤维化和全身不适。目前没有 可用于淋巴水肿的药物治疗。然而，LTB4（花生四烯酸的代谢产物） 与淋巴水肿的发展有关，并被确定为可能的药物靶点。的目标 本研究旨在确定 LTB4 是否会导致淋巴集合管衰竭并确定其直接机制 LTB4 对淋巴集合管的作用。假设 LTB4 抑制淋巴集合管 受伤后发生高浓度收缩，导致淋巴功能不全和极端 肿胀见于淋巴水肿。我们预测 LTB4 的这种功能作用通过两种机制发生： LTB4 直接作用于淋巴集合管抑制泵送，LTB4 驱动巨噬细胞募集 已知，通过分泌 VEGFC 和 iNOS 进一步放大疾病进展 淋巴功能的效应器。 为了测试 LTB4 浓度如何影响淋巴集合管功能，我们将首先使用分离的 血管设置以测试不同浓度的 LTB4 对淋巴管张力和收缩力的直接影响。 我们还将确定 LTB4 对淋巴管收缩力的影响是否是由其受体 BLT1 介导的 和/或 BLT2。接下来，一种名为 bestatin 的 LTB4 拮抗剂将与单血管结扎结合使用 小鼠淋巴水肿模型，用于研究 LTB4 在疾病进展过程中如何影响集合血管功能。在 单血管结扎模型，主要集合血管和周围初始淋巴管将 烧灼，同时保留一个收集容器完好无损。通过使用近红外成像技术来测量收缩 手术后该集合血管的功能，LTB4拮抗剂对手术期间收缩功能的影响 可以确定疾病进展。该手术模型将在遗传性巨噬细胞耗竭中进行测试 小鼠模型检查 LTB4 对集合血管泵功能是否存在巨噬细胞介导的影响 在淋巴水肿发展过程中。巨噬细胞的 VEGFC 分泌和 iNOS 表达将在 LTB4 拮抗作用的背景以确定巨噬细胞调节淋巴管的机制 功能。这项研究的结果将有助于阐明 LTB4 在淋巴水肿发展中的作用， 描述其对淋巴系统功能的直接影响，并确定 LTB4 的多种机制 导致淋巴集合管泵故障。这些结果将是迈向更好的重要一步 了解淋巴水肿的进展，并将指导药物治疗的使用 针对 LTB4 及其代谢的淋巴水肿。研究培训将在佐治亚研究所进行 Technology，世界一流的研究机构，拥有充足的设施和资源来帮助指导年轻的研究人员 走向学术界的职业生涯。