Molecular mechanisms enhancing lymphatic valve formation

增强淋巴瓣形成的分子机制

• 批准号: 10331300
• 负责人: Ying Yang
• 金额: $ 37.47万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10331300
• 关键词: Ablation; Adipose tissue; Adult; Affect; Animal Model; Cancer Patient; Cancer Survivor; Chronic; Chronic Disease; Connexin 43; DNA Sequence Alteration; Data; Deposition; Disease; Disease model; Economics; Embryo; Excision; Exhibits; FOXC2 gene; FOXO1A gene; FRAP1 gene; Fibrosis; Gene Mutation; Genes; Genetic; Genetic Transcription; Goals; Growth; Human; Immune response; Impairment; Infection; Innovative Therapy; Knockout Mice; Laboratories; Lead; Liquid substance; Lymph; Lymph Node Dissections; Lymphangiography; Lymphatic; Lymphatic Endothelial Cells; Lymphatic function; Lymphedema; Maintenance; Malignant Neoplasms; Mediating; Modeling; Molecular; Molecular Target; Morphology; Mus; Operative Surgical Procedures; Outcome; Pathologic; Pathway interactions; Patients; Persons; Pharmacology; Phenotype; Prevention strategy; Role; Signal Pathway; Signal Transduction; Swelling; Symptoms; Tamoxifen; Testing; Time; Tissues; Western Blotting; druggable target; effective therapy; human disease; inhibitor; insight; lymph flow; lymph nodes; lymph stasis; lymphatic valve; lymphatic vasculature; lymphatic vessel; mTOR Signaling Pathway; mouse model; new therapeutic target; novel; postnatal; prevent; response; shear stress; small molecule; targeted treatment; transcription factor

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.

淋巴水肿是一种慢性疾病，是由功能失调的淋巴管引起的，可以由 遗传突变或身体损害。该疾病仅在美国就影响3-5万人， 大多数是进行淋巴结去除手术的癌症生存。没有有效的治疗方法 淋巴水肿，也没有任何预防策略。症状包括由于脂肪组织而严重肿胀的组织 沉积和纤维化，导致患者的免疫激发和反复感染受损。 大量研究表明，慢性淋巴结将成为淋巴水肿。淋巴流量受损 小鼠引起淋巴瓣的消退，因为需要恒定流动介导的信号 淋巴瓣膜小叶的形成和持续维护。此外，仅保持前进淋巴流量 通过定期间隔的腔内瓣膜（LEC）衍生的腔内瓣膜（LEC）。淋巴管造影 先天性或获得性淋巴水肿的人类患者的特征是逆行淋巴流动， 这极大地暗示有缺陷或回归淋巴瓣是病变因子。那是重要的 未满足的需求是防止淋巴瓣回归和/或刺激淋巴瓣形成以治疗 淋巴水肿。令人惊讶的是，关于如何响应流体激活阀门基因的知之甚少 剪切应力。我们已经确定了用作淋巴瓣复制品的第一个转录因子 形成FOXO1，并表明从LEC中的FOXO1遗传缺失增加了淋巴瓣的数量 显著地。我们的数据是第一个证明任何基因的消融能够增加数量的数据 形态上正常的淋巴瓣。那就是FOXO1途径的抑制剂代表高度有价值的 增强阀形成的药理靶标。我们的中心假设是删除FOXO1将 通过上调已知阀形成基因并将恢复瓣膜来增加淋巴瓣的数量 在淋巴水肿的动物模型中的功能。该假设将通过以下三个目标进行检验：目标1 将确定FOXO1损失增强淋巴瓣形成的机制，AIM 2将确定 与FOXO1相关的信号通路，增加了淋巴瓣形成，AIM 3将分析 淋巴瓣在缺乏FOXO1的健康和淋巴小鼠中的功能。高度期待 这些目标将提供有关FOXO1在调节阀形成和功能中的作用的新颖见解， 最终将导致鉴定可吸毒靶标和创新疗法，以治疗患者 淋巴水肿通过增加瓣膜的生长和功能。