FOXC2 in Hereditary Lymphedema and Lymphatic Development

遗传性淋巴水肿是淋巴系统的发育障碍，导致毁容， 四肢的致残性水肿（肿胀）以及各种相关的异常。大多数是常染色体的 显性，表现和发病年龄可变。在这些条件下的主要目标组织是淋巴 系统，血管系统的一个知之甚少的组成部分，负责排出的液体的微循环 从组织和返回到血管系统，以及用于运输免疫系统的细胞。尽管 在先天性和获得性疾病（包括癌症）中的重要性，对分子事件知之甚少 参与淋巴系统的发育。与许多其他发育途径一样， 遗传性水肿可以提供对淋巴管生成所涉及的分子事件的重要认识。 我们最近确定了遗传性双列吸虫病（LD）的基因负责。这种疾病 特征为水肿和睑板腺长出的多排睫毛。关联 畸形包括法洛四联症、腭裂、胎儿水肿和囊状水瘤。致病基因 LD是FOXC 2叉头家族转录因子。本项目的总体目标是确定 FOXC 2在遗传性水肿和哺乳动物淋巴系统发育中的作用初步数据 表明Foxc 2 +/-小鼠具有高度异常的淋巴管和淋巴结，类似于 病人有LD。具体目标是：（1）充分表征Foxc 2 +/-和-/-小鼠以及转基因小鼠 过表达该基因，用于淋巴异常，作为双股丝虫病的模型系统和异常 哺乳动物淋巴系统发育的研究;（2）确定Foxc 2在淋巴系统中的表达模式 开始评估Foxc 2不足对淋巴表型的机制， （3）开始确定Foxc 2在基因调控的途径和层次中的作用 哺乳动物中的淋巴管生成;（4）评估淋巴和其他异常中Foxc 2缺陷的时间 通过制造Foxc 2在发育过程中有条件表达的小鼠。从这些研究中，我们将了解到 由Foxc 2缺陷引起的小鼠淋巴系统发育中的精确缺陷，无论Foxc 2 在淋巴细胞或其他细胞类型中的表达与这些缺陷相关，Foxc 2不足的时间在淋巴细胞或其他细胞类型中的表达与这些缺陷相关。 表型，并将开始确定Foxc 2在复杂的生化途径中的作用， 淋巴管生成

The hereditary lymphedemas are developmental disorders of the lymphatic system that lead to disfiguring and often disabling edema (swelling) of the extremities together with various associated abnormalities. Most are autosomal dominant with variable expression and age of onset. The primary target tissue in these conditions is the lymphatic system, a poorly understood component of the vascular system responsible for microcirculation of fluids drained from tissues and the return to the blood vascular system, and for trafficking cells of the immune system. Despite its importance in congenital and acquired disease, including cancer, very little is known about the molecular events involved in development of the lymphatic system. As with many other developmental pathways, genes involved in hereditary lymphedema can provide important insights into the molecular events involved in lymphangiogenesis. We recently identified the gene responsible for hereditary lymphedema-distichiasis (LD). This disorder is characterized by lymphedema and extra rows of eyelashes arising from the Meibomian glands. Associated abnormalities include tetralogy of Fallot, cleft palate, hydrops fetalis and cystic hygroma. The gene responsible for LD is the FOXC2 forkhead family transcription factor. The overall goals of this project are to determine the role of FOXC2 in hereditary lymphedema and in the development of the mammalian lymphatic system. Preliminary data indicates that Foxc2+/- mice have highly abnormal lymphatic vessels and lymph nodes analogous to those in patient's with LD. Specific aims are: (1) to fully characterize Foxc2 +/- and -/- mice, and transgenic mice overexpressing the gene, for lymphatic abnormalities as a model system for lymphedema-distichiasis and abnormal lymphatic development in mammals; (2) to determine the expression patterns of Foxc2 in the lymphatic system during development to begin to assess the mechanism of Foxc2 insufficiency on lymphatic phenotype and development; (3) to begin to establish the role of Foxc2 in the pathways and hierarchy of genes controlling lymphangiogenesis in mammals; (4) to assess the timing ofFoxc2 deficiency in lymphatic and other abnormalities by creating mice in which Foxc2 is conditionally expressed during development. From these studies we will learn the precise defects in the developing mouse lymphatic system caused by Foxc2 deficiency, whether Foxc2 expression in lymphatic or other cell types is correlated with these defects, the timing of Foxc2 insufficiency on phenotype, and will begin to determine the role of Foxc2 in the complex biochemical pathways involved in lymphangiogenesis.