Molecular mechanisms enhancing lymphatic valve formation

淋巴水肿是一种慢性疾病，由淋巴血管系统功能障碍引起，可发生于 要么是基因突变，要么是身体损伤。仅在美国就有300-500万人感染这种疾病， 大多数是接受过淋巴结切除手术的癌症幸存者。目前还没有有效的治疗方法 淋巴水肿，也没有任何预防策略。症状包括脂肪组织引起的组织严重肿胀。 沉积和纤维化，导致患者免疫反应受损和反复感染。 许多研究已经证实，慢性淋巴淤积会导致淋巴水肿。淋巴流入受损 小鼠导致淋巴瓣膜的退化，因为持续的流动介导的信号是需要的 淋巴瓣小叶的形成和持续维护。此外，仅维持前向淋巴流动。 通过来自淋巴管内皮细胞(LEC)的规则间隔的管腔内瓣膜。淋巴管造影术 人类先天性或获得性淋巴水肿患者的特点是淋巴流逆行， 这强烈地表明淋巴瓣膜缺陷或退化是一个致病因素。因此，一个重要的 未满足的需要是防止淋巴瓣退化和/或刺激淋巴瓣形成以治疗 淋巴浮肿。令人惊讶的是，关于瓣膜形成基因是如何被液体激活的，人们知之甚少。 剪切力。我们已经确定了第一个作为淋巴瓣抑制因子的转录因子。 Foxo1的形成，并表明LEC中Foxo1的基因缺失增加了淋巴瓣的数量 意义重大。我们的数据首次表明，任何基因的去除都能够增加细胞的数量 形态正常的淋巴瓣膜。因此，Foxo1途径的抑制剂具有很高的价值 增强瓣膜形成的药理作用靶点。我们的中心假设是，删除Foxo1将 通过上调已知的瓣膜形成基因来增加淋巴瓣的数量，并将恢复瓣膜 在淋巴水肿动物模型中发挥作用。这一假设将通过以下三个目标进行检验：目标1 将确定Foxo1的缺失促进淋巴瓣形成的机制，目标2将确定 Foxo1相关的信号通路，增加淋巴瓣的形成，Aim 3将分析 健康和缺乏Foxo1的淋巴水肿症小鼠的淋巴瓣膜功能。备受期待的是 这些目标将为Foxo1在调节瓣膜形成和功能中的作用提供新的见解， 最终将导致确定可用药的靶点和治疗患者的创新疗法 通过增加瓣膜的生长和功能而引起的淋巴水肿。

Lymphedema is a chronic disease that is caused by a dysfunctional lymphatic vasculature, and can occur from either genetic mutations or physical damage. The disease affects 3-5 million people in the US alone, and the majority are cancer survivors who had lymph node removal surgery. There are no effective treatments for lymphedema, nor any prevention strategies. Symptoms include severely swollen tissues due to adipose tissue deposition and fibrosis, resulting in an impaired immune response and recurring infections in patients. Numerous studies have established that chronic lymph stasis begets lymphedema. Impaired lymph flow in mice causes the regression of lymphatic valves because constant flow-mediated signals are required for the formation and ongoing maintenance of lymphatic valve leaflets. Further, forward lymph flow is maintained only by regularly spaced intraluminal valves derived from lymphatic endothelial cells (LEC). Lymphangiography of human patients with either congenital or acquired lymphedema is characterized by retrograde lymph flow, which strongly implicates defective or regressing lymphatic valves as a causative factor. Thus, a significant unmet need is to prevent lymphatic valve regression and/or stimulate lymphatic valve formation to treat lymphedema. Surprisingly little is known about how valve-forming genes are activated in response to fluid shear stress. We have identified the first transcription factor that acts as a repressor of lymphatic valve formation, Foxo1, and show that genetic deletion of Foxo1 from LEC increases the number of lymphatic valves significantly. Our data are the first to show that the ablation of any gene is capable of increasing the number of morphologically normal lymphatic valves. Thus, inhibitors of the Foxo1 pathway represent highly valuable pharmacologic targets to enhance valve formation. Our central hypothesis is that deletion of Foxo1 will increase the number of lymphatic valves by upregulating known valve-forming genes and will restore valve function in an animal model of lymphedema. This hypothesis will be tested by the following three aims: Aim 1 will determine the mechanisms by which loss of Foxo1 enhances lymphatic valve formation, Aim 2 will identify Foxo1-associated signaling pathways that increase lymphatic valve formation, and Aim 3 will  analyze the function of lymphatic valves in healthy and lymphedematous mice lacking Foxo1. It is highly anticipated that these aims will provide novel insights into the role of Foxo1 in regulating valve formation and function, which will ultimately lead to the identification of a druggable target and innovative therapy to treat patients with lymphedema by augmenting valve growth and function.