FOXC2 in Hereditary Lymphedema and Lymphatic Development

描述(申请人提供)：遗传性淋巴水肿是淋巴系统的发育障碍，导致肢体的毁容，通常是致残的水肿(肿胀)以及各种相关的异常。大多数是常染色体显性遗传，有不同的表达和发病年龄。在这些情况下，主要的靶组织是淋巴系统，淋巴系统是血管系统中一个鲜为人知的组成部分，负责从组织中排出的液体的微循环和返回血管系统，以及免疫系统的细胞运输。尽管它在先天性和获得性疾病(包括癌症)中很重要，但人们对淋巴系统发育过程中涉及的分子事件知之甚少。与许多其他发育途径一样，涉及遗传性淋巴水肿的基因可以为研究涉及淋巴管生成的分子事件提供重要的见解。我们最近发现了遗传性淋巴水肿-二叉神经症(LD)的致病基因。这种疾病的特征是淋巴水肿和眉毛腺长出的额外的几排睫毛。相关异常包括法洛四联症、腭裂、胎儿积水和囊性水瘤。导致LD的基因是FOXC2叉头家族转录因子。该项目的总体目标是确定FOXC2在遗传性淋巴水肿和哺乳动物淋巴系统发育中的作用。初步数据表明，FOXC2+/-小鼠具有与LD患者相似的高度异常的淋巴管和淋巴结节。具体目标是：(1)全面鉴定FOXC2+/-和-/-小鼠以及过表达该基因的转基因小鼠，作为研究淋巴异常的模型系统；(2)确定FOXC2在发育过程中淋巴系统的表达模式，以开始评估FOXC2不足对淋巴表型和发育的影响机制；(3)开始确定FOXC2在哺乳动物淋巴管生成控制基因的途径和层次中的作用；(4)通过建立在发育过程中有条件地表达FOXC2的小鼠，评估FOXC2缺陷在淋巴和其他异常中的发生时间。从这些研究中，我们将了解FOXC2缺乏在发育中的小鼠淋巴系统中的确切缺陷，FOXC2在淋巴管或其他细胞类型中的表达是否与这些缺陷相关，FOXC2缺乏的时间对表型的影响，并将开始确定FOXC2在涉及淋巴管生成的复杂生化途径中的作用。

DESCRIPTION (provided by applicant): 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 of Foxc2 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.