Fox Transcription factors in lymphatic vessel development

Fox 淋巴管发育中的转录因子

• 批准号: 8867008
• 负责人: Tsutomu Kume
• 金额: $ 38.63万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8867008
• 关键词: Boxing; Cardinal vein; Cardiovascular system; Cell Proliferation; Cell physiology; Cells; Complex; Congenital Abnormality; Data; Development; Disease; Drainage procedure; Embryo; Etiology; Eyelash; Failure; Family; Foxes; Gene Expression Profile; Genes; Genetic; Goals; Grant; Growth; Homeostasis; Human; Hyperplasia; Immunologic Surveillance; In Vitro; Inflammatory; Knock-in Mouse; Lead; Limb structure; Lipids; Liquid substance; Lymph; Lymphangiogenesis; Lymphatic; Lymphatic Diseases; Lymphatic Endothelial Cells; Lymphatic System; Lymphatic vessel; Lymphedema; MAP Kinase Gene; MEKs; Maintenance; Mesentery; Mission; Modeling; Molecular; Morphogenesis; Morphology; Mus; Mutation; Nature; Neoplasm Metastasis; Notch Signaling Pathway; Obstruction; Outcome; Pathologic Processes; Pathway interactions; Patient Care; Play; Public Health; Research; Risk; Role; Semaphorin-3A; Signal Pathway; Signal Transduction; Swelling; Syndrome; System; Testing; Tissues; Vascular System; Venous; absorption; apoAI regulatory protein-1; gastrointestinal system; genome-wide; in vivo; inhibitor/antagonist; insight; interstitial; member; mutant; notch protein; novel strategies; novel therapeutics; postnatal; prevent; progenitor; public health relevance; research study; transcription factor; transcriptome sequencing; tumor

 DESCRIPTION (provided by applicant): The lymphatic vascular system is essential for lipid absorption/transport from the digestive system, maintenance of tissue fluid homeostasis, and immune surveillance. It is also involved in many pathological processes such as inflammatory disease and tumor metastasis, as well as lymphedema, in which the drainage of lymphatic fluid from the interstitial tissue is insufficient, causing the tissues to swell. Lymphedema is most commonly attributed to impaired lymphangiogenesis or lymphatic-valve deficiency; however, the complex nature of lymphatic vessel abnormalities and disease remain poorly understood. Thus, our long-term goal is to understand the molecular and cellular mechanisms responsible for the formation and function of the lymphatic vascular system. FoxC1 and FoxC2 are closely related members of the Fox (Forkhead box) transcription factor family, and our group has previously shown that murine Foxc1 and Foxc2 have numerous essential roles in cardiovascular development. Mutations in human FOXC2 are responsible for the autosomal dominant syndrome Lymphedema-distichiasis, which is characterized by the obstruction of lymphatic drainage in the limbs, venous valve failure, and the growth of an extra set of eyelashes. Recent studies have shown that Foxc2 is also essential for lymphatic valve formation, but the role of FoxC1 in the lymphatic system has yet to be defined. Thus, we have recently generated mice that carry lymphatic endothelial cell (LEC)-specific mutations for Foxc1, Foxc2, or both, which will enable us to determine the precise functions of Foxc1 and Foxc2 in the cellular processes that lead to the development of lymphatic vessels. Our initial studies indicate that the loss of Foxc1 and Foxc2, alone or in combination, leads to lymphatic hyperplasia and is accompanied by declines in the expression of RasGAP genes and by the hyperactivation of ERK. Furthermore, our new genome-wide RNA-seq analysis indicates that Notch signaling genes such as Notch1 and Dll4 are significantly downregulated in LECs that have been isolated from conditional compound LEC-Foxc1;LEC-Foxc2 mutants. Thus, the objective of this application is to study the role of the transcription factors Foxc1 and Foxc2 in lymphatic vessel development. Our central hypothesis is that Foxc1 and Foxc2 are essential for lymphatic cell fate determination, lymphangiogenesis, and lymphatic valve development, and we will test our central hypothesis and accomplish the objective of this application by pursuing the following three Specific Aims: 1) To determine whether Foxc1 and Foxc2 participate in lymphatic cell fate determination by interacting with the Notch signaling pathway. 2) To define the mechanisms by which Foxc1 and Foxc2 regulate the Ras/ERK pathway during lymphangiogenesis. 3) To elucidate the cooperative and distinct functions of Foxc1 and Foxc2 in lymphatic valve development. In summary, the outcome of our project is an extensive characterization of the critical roles that Foxc1 and Foxc2 play in lymphatic vessel development. We expect our findings to have an important positive impact on patient care, because completion of the proposed studies will likely lead to the development and refinement of novel strategies for preventing and treating lymphatic disorders, such as lymphedema.

 描述（由申请人提供）：淋巴血管系统对于吸收脂质/从消化系统运输、维持组织液稳态和免疫监视至关重要，它还参与许多病理过程，例如炎症性疾病和肿瘤转移。以及淋巴水肿，其中淋巴液从间质组织排出不足，导致组织肿胀，淋巴水肿最常见的原因是淋巴管生成或淋巴瓣膜受损。然而，我们对淋巴管异常和疾病的复杂性质仍知之甚少，因此，我们的长期目标是了解与 FoxC1 和 FoxC2 密切相关的分子和细胞机制。 Fox（叉头盒）转录因子家族的成员，我们的研究小组之前已证明小鼠 Foxc1 和 Foxc2 在心血管发育中具有许多重要作用。人类 FOXC2 的突变是导致常染色体显性综合征的原因。淋巴水肿-双歧病，其特征是四肢淋巴引流受阻、静脉瓣膜衰竭以及额外一组睫毛的生长。最近的研究表明，Foxc2 对于淋巴瓣膜的形成也至关重要，但 FoxC1 的作用较弱。因此，我们最近培育出了携带 Foxc1、Foxc2 或两者的淋巴内皮细胞 (LEC) 特异性突变的小鼠。确定 Foxc1 和 Foxc2 在导致淋巴管发育的细胞过程中的精确功能，我们的初步研究表明，Foxc1 和 Foxc2 单独或组合的丧失会导致淋巴管增生，并伴有淋巴管增殖的下降。此外，我们新的全基因组 RNA-seq 分析表明，Notch 信号基因（例如 Notch1 和 Dll4）在 LEC 中显着下调。已从条件化合物 LEC-Foxc1；LEC-Foxc2 突变体中分离出来。因此，本应用的目的是研究转录因子 Foxc1 和 Foxc2 在淋巴管发育中的作用。淋巴细胞命运决定、淋巴管生成和淋巴瓣发育，我们将通过追求以下三个具体目标来检验我们的中心假设并实现本应用的目标：1) 确定 Foxc1 和Foxc2 通过与 Notch 信号通路相互作用参与淋巴细胞命运决定 2) 明确 Foxc1 和 Foxc2 在淋巴管生成过程中调节 Ras/ERK 通路的机制 3) 阐明 Foxc1 和 Foxc2 在淋巴管中的协同和独特功能。总之，我们项目的结果是对 Foxc1 和 Foxc2 在淋巴管发育中发挥的关键作用的广泛表征，我们期望我们的发现对淋巴管发育产生重要的积极影响。患者护理，因为完成拟议的研究可能会导致预防和治疗淋巴疾病（例如淋巴水肿）的新策略的开发和完善。