Fox Transcription factors in lymphatic vessel development

Fox 淋巴管发育中的转录因子

• 批准号: 9132839
• 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/9132839
• 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; Genes; Genetic; Goals; Grant; Growth; Health; Homeostasis; Human; Hyperplasia; Immunologic Surveillance; In Vitro; Inflammatory; Knock-in; 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 therapeutic intervention; postnatal; prevent; progenitor; research study; transcription factor; transcriptome; 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（由申请方提供）：淋巴管系统对于消化系统的脂质吸收/转运、组织液稳态维持和免疫监视至关重要。它还参与许多病理过程，如炎性疾病和肿瘤转移，以及水肿，其中淋巴液从间质组织的引流不足，导致组织肿胀。淋巴水肿最常见的原因是淋巴管生成受损或淋巴管瓣缺陷;然而，淋巴管异常和疾病的复杂性质仍然知之甚少。因此，我们的长期目标是了解负责淋巴管系统的形成和功能的分子和细胞机制。FoxC 1和FoxC 2是Fox（叉头盒）转录因子家族的密切相关成员，我们的研究小组先前已经表明，小鼠Foxc 1和Foxc 2在心血管发育中具有许多重要作用。人类FOXC 2的突变导致常染色体显性综合征淋巴水肿-双睫状体病，其特征在于肢体淋巴引流受阻、静脉瓣膜衰竭和多出一组睫毛。最近的研究表明，Foxc 2也是淋巴阀形成所必需的，但FoxC 1在淋巴系统中的作用尚未确定。因此，我们最近已经产生了携带淋巴管内皮细胞（LEC）特异性Foxc 1，Foxc 2或两者突变的小鼠，这将使我们能够确定Foxc 1和Foxc 2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，Foxc 1和Foxc 2的丢失，单独或组合，导致淋巴增生，并伴随着RasGAP基因表达的下降和ERK的过度激活。此外，我们新的全基因组RNA-seq分析表明，Notch信号传导基因如Notch 1和Dll 4在从条件化合物LEC-Foxc 1; LEC-Foxc 2突变体分离的LEC中显著下调。因此，本申请的目的是研究转录因子Foxc 1和Foxc 2在淋巴管发育中的作用。我们的中心假设是Foxc 1和Foxc 2对于淋巴细胞命运决定、淋巴管生成和淋巴瓣发育是必需的，并且我们将通过追求以下三个具体目的来测试我们的中心假设并实现本申请的目的：1）确定Foxc 1和Foxc 2是否通过与Notch信号传导途径相互作用而参与淋巴细胞命运决定。2)明确Foxc 1和Foxc 2在淋巴管生成过程中调节Ras/ERK通路的机制。3)探讨Foxc 1和Foxc 2在淋巴管瓣发育中的协同作用和独特功能。总之，我们项目的结果是Foxc 1和Foxc 2在淋巴管发育中发挥的关键作用的广泛表征。我们希望我们的研究结果对患者护理产生重要的积极影响，因为完成拟议的研究可能会导致预防和治疗淋巴系统疾病（如水肿）的新策略的开发和完善。