Specification And Patterning of the Lymphatic System

淋巴系统的规格和模式

• 批准号: 10690345
• 负责人: Brant Weinstein
• 金额: $ 48万
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10690345
• 关键词: Anatomy; Animal Model; Animals; Blood; Blood Vessels; Brain; Cardiovascular system; Cephalic; Characteristics; Clinical; Development; Drainage procedure; Embryo; Experimental Models; Fatty acid glycerol esters; Fishes; Fluid Balance; Gene Expression; Genes; Genetic; Goals; Growth; Homeostasis; Human; Image; Imaging Device; Immune response; Larva; Lead; Liquid substance; Lymph; Lymphangiogenesis; Lymphatic; Lymphatic Endothelium; Lymphatic System; Lymphedema; Lymphocyte; Malignant Neoplasms; MicroRNAs; Modeling; Molecular; Morphology; Neoplasm Metastasis; Optics; Pathologic Processes; Pathology; Pattern; Pericytes; Phenotype; Population; RNA; Regulation; Resolution; Role; Route; Structure; Systems Development; Tissues; Transgenic Organisms; Trees; Vascular System; Venous; Vertebrates; Visualization; Work; Zebrafish; absorption; blind; genetic analysis; high resolution imaging; imaging study; in vivo; in vivo Model; in vivo imaging; insight; interest; lymphatic development; lymphatic vasculature; lymphatic vessel; microscopic imaging; mutant; novel; progenitor; tool; tumor

Our identification and characterization of a lymphatic vascular system in the zebrafish made it possible to bring the powerful genetic, experimental embryologic, and imaging tools available in this model organism to bear on the question of how lymphatic vessels form and what regulates their growth and assembly. Understanding how to regulate and control lymphatic vessel formation is a topic of considerable clinical interest given recent evidence suggesting that lymphatics are the major route for tumor metastasis in many if not most cancers. The long-term goal of this project is to expand on our preliminary findings in order to gain a more detailed understanding of how lymphatic vessels assemble in the fish, and then use this powerful model to study how lymphangiogenesis is regulated in vivo. The lymphatic system has become a subject of great interest in recent years because of its important role in normal and pathological processes, but progress in understanding the origins and early development of this system has been hampered by difficulties in observing lymphatic cells in vivo and performing defined genetic and experimental manipulation of the lymphatic system in currently available model organisms. We demonstrated that the zebrafish possesses a lymphatic system that shares many of the morphological, molecular, and functional characteristics of the lymphatic vessels found in other vertebrates (including humans), providing a superb model for imaging and studying lymphatic development. We have used the genetic and experimental advantages fo the fish to examine the origins of lymphatic progenitors and uncover mechanisms directing the assembly and patterning of lymphatic vascular networks. We are currently pursuing further study of the formation of the lymphatic system through a number of ongoing projects: 1. We are performing high-resolution imaging of transgenic lines we generated that permit direct, specific visualization of the developing lymphatic vasculature to further characterize how the lymphatic vascular system grows and assembles during development. 2. We are studying mutants with lymphatic vessel phenotypes to uncover the roles of novel genes important for lymphatic development. 3. We are analyzing global and tissue-specific patterns of lymphatic gene expression using newly developed transgenic tools that facilitate lymphatic-specific profiling. 4. We are characterizing and studying novel microRNAs expressed in the lymphatic endothelium, with the goal of uncovering how these small regulatory RNAs influence gene expression in the lymphatic vasculature. 5. We are studying an unusual brain perivascular cell population derived from venous-lymphatic endothelium that we have identified. 6. We are studying the formation and function of novel cranial lymphatic networks in the zebrafish and how they support brain function and homeostasis. The results of our studies, combining the genetic and experimental tools available in the zebrafish with the ability to perform high-resolution microscopic imaging of developing vascular structures in living animals, will continue to lead to important new insights into the origins and growth of the lymphatic system and reveal the molecular mechanisms critical for lymphatic development and lymphatic pathologies.

我们对斑马鱼中淋巴管系统的鉴定和表征使该模型有机体中可用的强大遗传，实验性胚胎学和成像工具成为可能，以解决淋巴管如何形成以及如何调节其生长和组装的问题。鉴于最近的证据表明，在许多癌症中，了解淋巴管是肿瘤转移的主要途径，因此了解如何调节和控制淋巴管的形成是一个相当大的临床兴趣的话题。该项目的长期目标是扩大我们的初步发现，以便对淋巴管如何在鱼中组装，然后使用这种强大的模型来研究如何在体内调节淋巴管生成。 由于淋巴系统在正常和病理过程中的重要作用，淋巴系统已成为引起人们兴趣的主题，但是在了解该系统的起源和早期发展方面的进展受到了在体内观察淋巴细胞的困难，并在当前可用模型生物体中对淋巴细胞进行了观察并执行确定的遗传和实验性操纵。我们证明斑马鱼具有一个淋巴系统，该系统具有在其他脊椎动物（包括人）中发现的淋巴管的许多形态，分子和功能特征，为成像和研究淋巴发育提供了出色的模型。我们已经使用了鱼类的遗传和实验优势来检查淋巴祖细胞的起源，并发现了指导淋巴血管网络组装和模式的机制。 我们目前正在通过许多正在进行的项目进一步研究淋巴系统的形成： 1。我们正在对转基因线进行高分辨率成像，以允许对发育中的淋巴脉管系统进行直接的，特定的可视化，以进一步表征淋巴管系统在发育过程中的生长和组装方式。 2。我们正在研究具有淋巴血管表型的突变体，以发现新型基因对淋巴发育重要的作用。 3。我们正在使用新开发的转基因工具来分析淋巴基因表达的全球和组织特异性模式，以促进淋巴特异性分析。 4。我们正在描述和研究在淋巴内皮中表达的新型microRNA，目的是揭示这些小的调节性RNA如何影响淋巴管中的基因表达。 5。我们正在研究我们已经鉴定出的来自静脉 - 淋巴内皮细胞的异常脑周围细胞群体。 6。我们正在研究斑马鱼中新型颅淋巴网络的形成和功能以及它们如何支持大脑功能和稳态。 我们的研究结果将斑马鱼中可用的遗传和实验工具与对活动物中发展血管结构进行高分辨率显微成像的能力相结合，将继续导致对淋巴系统的起源和生长的重要新见解，并揭示淋巴发育和淋巴发育和淋巴性病理学关键机制。