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.

我们对斑马鱼淋巴管系统的识别和表征使得我们能够利用该模型生物中强大的遗传、实验胚胎学和成像工具来解决淋巴管如何形成以及调节其生长和组装的问题。鉴于最近的证据表明淋巴管是许多（如果不是大多数）癌症中肿瘤转移的主要途径，了解如何调节和控制淋巴管形成是临床上相当感兴趣的话题。该项目的长期目标是扩展我们的初步发现，以便更详细地了解鱼体内淋巴管的组装方式，然后利用这个强大的模型来研究体内淋巴管生成的调节方式。 近年来，淋巴系统因其在正常和病理过程中的重要作用而成为人们极大兴趣的课题，但由于观察体内淋巴细胞和执行定义的淋巴细胞的困难，对该系统起源和早期发展的理解进展受到阻碍。目前可用的模型生物体中淋巴系统的遗传和实验操作。我们证明，斑马鱼拥有的淋巴系统与其他脊椎动物（包括人类）中发现的淋巴管具有许多形态、分子和功能特征，为成像和研究淋巴发育提供了极好的模型。我们利用鱼的遗传和实验优势来检查淋巴祖细胞的起源，并揭示指导淋巴血管网络组装和模式化的机制。 我们目前正在通过一些正在进行的项目进一步研究淋巴系统的形成： 1. 我们正在对我们产生的转基因系进行高分辨率成像，从而可以直接、具体地观察发育中的淋巴管系统，以进一步表征淋巴管系统在发育过程中如何生长和组装。 2. 我们正在研究具有淋巴管表型的突变体，以揭示对淋巴管发育重要的新基因的作用。 3. 我们正在使用新开发的转基因工具分析淋巴基因表达的全局和组织特异性模式，以促进淋巴特异性分析。 4. 我们正在表征和研究淋巴内皮中表达的新型 microRNA，目的是揭示这些小调节 RNA 如何影响淋巴脉管系统中的基因表达。 5. 我们正在研究一种不寻常的脑血管周围细胞群，该细胞群源自我们已鉴定的静脉淋巴内皮。 6. 我们正在研究斑马鱼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体内平衡。 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体动物中正在发育的血管结构进行高分辨率显微成像的能力相结合，将继续为淋巴管的起源和生长提供重要的新见解。系统并揭示对淋巴发育和淋巴病理至关重要的分子机制。