Modulation of Lymphatic System Function by LTB4

淋巴水肿是一种毁灭性的疾病，主要影响乳腺癌患者术后 手术会导致四肢肿胀、组织纤维化和全身不适。确实有 目前还没有针对淋巴水肿的药物治疗方法。然而，LTB4，一种新陈代谢产物 花生四烯酸与淋巴水肿的发生有关，并被确定为一种可能的药物。 目标。本研究的目的是确定LTB4是否导致淋巴收集血管衰竭，并确定 LTB4对淋巴管的直接作用机制。假设是LTB4抑制了 淋巴集合管在损伤后发生高浓度收缩，导致淋巴管 淋巴水肿时出现的功能不全和极度肿胀。我们预测LTB4的这种功能效应 通过两种机制发生：LTB4直接作用于淋巴收集血管以抑制泵送； LTB4推动巨噬细胞募集到损伤部位，进一步放大疾病进展 分泌已知的淋巴功能效应物VEGFC和iNOS。 为了测试LTB4浓度如何影响淋巴管收集功能，我们将首先使用一个分离的 血管设置，以测试不同浓度的LTB4对淋巴管张力和 伸缩性。我们还将确定LTB4对淋巴管收缩的影响是否通过其介导 受体，BLT1和/或BLT2。接下来，名为Best atin的LTB4拮抗剂将与一种 小鼠单血管结扎淋巴水肿模型研究LTB4对集合管功能的影响 疾病的发展。在单血管结扎模型中，优势收集血管及其周围 最初的淋巴管将被烧灼，而一根收集血管将保持完好。通过使用近红外成像 测量收集血管术后收缩功能的技术--LTB4的作用 可以确定疾病进展过程中对收缩功能的拮抗作用。这个手术模型将是 在遗传性巨噬细胞耗竭小鼠模型中进行测试，以检查是否存在巨噬细胞介导的效应 LTB4在淋巴水肿形成过程中对收集血管泵功能的影响。血管内皮生长因子分泌与诱导型一氧化氮合酶 巨噬细胞的表达将在LTB4拮抗的背景下进行量化，以确定 巨噬细胞调节淋巴功能的机制。这项研究的结果将有助于 阐明LTB4在淋巴水肿发生发展中的作用，表征其对淋巴的直接作用 系统功能，并确定LTB4驱动淋巴管收集管泵的多种机制 失败了。这些结果将是更好地理解淋巴水肿的重要一步。 进展并将为针对LTB4的淋巴水肿药物治疗的使用提供信息 以及它的新陈代谢。研究培训将在世界一流的佐治亚理工学院进行 拥有充足设施和资源的研究机构，以帮助引导年轻研究人员在 学术界。

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.