FOXC2 in Hereditary Lymphedema and Lymphatic Development

FOXC2 在遗传性淋巴水肿和淋巴管发育中的作用

• 批准号: 6896853
• 负责人: THOMAS W GLOVER
• 金额: $ 40.27万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6896853
• 关键词: autoradiography; cell proliferation; cell type; developmental disease /disorder; gene expression; gene mutation; gene targeting; genetically modified animals; genotype; immunocytochemistry; in situ hybridization; laboratory mouse; lymphatic disorder; lymphatic system; lymphedema; magnetic resonance imaging; nucleic acid probes; polymerase chain reaction; transcription factor

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.

描述（由申请人提供）：遗传性四肢水肿是淋巴系统发育障碍，可导致四肢毁容和致残性水肿（肿胀）以及各种相关异常。大多数为常染色体显性遗传，表现和发病年龄可变。这些病症中的主要靶组织是淋巴系统，淋巴系统是血管系统的一个知之甚少的组成部分，负责从组织排出的流体的微循环和返回到血管系统，以及用于运输免疫系统的细胞。尽管它在先天性和获得性疾病（包括癌症）中的重要性，但对淋巴系统发育中涉及的分子事件知之甚少。与许多其他发育途径一样，遗传性水肿相关的基因可以为淋巴管生成相关的分子事件提供重要的见解。我们最近确定了遗传性双列吸虫病（LD）的基因负责。这种疾病的特点是水肿和额外的睫毛行从睑板腺产生。相关异常包括法洛四联症、腭裂、胎儿水肿和囊性水瘤。负责LD的基因是FOXC 2叉头家族转录因子。该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LD患者的淋巴管和淋巴结。具体目标是：（1）充分表征Foxc 2 +/-和-/-小鼠以及过表达该基因的转基因小鼠的淋巴异常，作为哺乳动物中双盲犬-双股吸虫病和异常淋巴发育的模型系统;（2）确定发育期间Foxc 2在淋巴系统中的表达模式，以开始评估Foxc 2不足对淋巴表型和发育的机制;（3）开始建立Foxc 2在哺乳动物中控制淋巴管生成的基因的通路和层次中的作用;（4）通过创建Foxc 2在发育期间条件性表达的小鼠来评估淋巴和其他异常中Foxc 2缺乏的时间。从这些研究中，我们将了解Foxc 2缺陷引起的小鼠淋巴系统发育中的精确缺陷，淋巴细胞或其他细胞类型中Foxc 2的表达是否与这些缺陷相关，Foxc 2不足表型的时间，并将开始确定Foxc 2在淋巴管生成中涉及的复杂生化途径中的作用。