Modulation of Lymphatic System Function by LTB4

项目摘要 淋巴水肿是一种毁灭性的疾病，主要影响乳腺癌术后患者， 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，花生四烯酸的代谢物LTB4已经 与淋巴水肿的发展有牵连，并被确定为可能的药物靶点。的目标是 本研究旨在确定LTB4是否导致淋巴收集血管衰竭，并确定其直接机制。 淋巴细胞转运蛋白4对淋巴管的作用。假设LTB4抑制淋巴收集血管 高浓度收缩发生在损伤后，导致淋巴供应不足和极端 淋巴水肿性肿胀。我们预测LTB4的这种功能作用通过两种机制发生； LTB4直接作用于淋巴收集血管以抑制泵送，并驱动巨噬细胞募集 损伤部位，通过分泌VEGFC和iNOS进一步放大疾病进展，已知 淋巴功能的效应器。 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对淋巴管张力和收缩的直接影响。 我们还将确定LTB4对淋巴管收缩的影响是否由其受体BLT1介导 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 建立小鼠淋巴水肿模型，研究LTB4在疾病进展过程中对集合管功能的影响。在……里面 单血管结扎模型，主要收集血管和周围的初始淋巴管 烧焦，而一个收集器皿将完好无损。通过使用近红外成像技术来测量收缩 LTB4拮抗剂对该收集血管术后收缩功能的影响 可以确定疾病的进展情况。这一手术模型将在遗传巨噬细胞耗竭中进行测试。 用小鼠模型检测LTB4是否具有巨噬细胞介导的血管泵功能 在淋巴水肿的发展过程中。巨噬细胞的VEGFC分泌和iNOS表达将在 LTB4拮抗作用背景下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在淋巴水肿发生中的作用， 表征其对淋巴系统功能的直接影响，并确定LTB4通过多种机制 导致淋巴管收集管泵故障。这些结果将是朝着更好的方向迈出的重要一步 了解淋巴水肿的进展并将为使用药物治疗提供信息 针对LTB4及其代谢的淋巴水肿。研究培训将在佐治亚理工学院进行 科技，一个世界级的研究机构，拥有充足的设施和资源来帮助指导年轻的研究人员 迈向学术界的事业。

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.