The Role of lymphatic endothelium in the developing thymus

淋巴内皮在胸腺发育中的作用

• 批准号: 10737333
• 负责人: Gay M Crooks
• 金额: $ 63.41万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-16 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10737333
• 关键词: Adult; Affect; Age; Aging; Architecture; Biological Assay; Blood; Blood Vessels; Blood capillaries; Categories; Cell Compartmentation; Cell Line; Cell Lineage; Cell surface; Cells; Complex; Data; Development; Discrimination; Disease; Embryo; Embryonic Development; Endothelial Cells; Endothelium; Event; Gene Expression; Gene Expression Profile; Genetic Transcription; Goals; Growth; Health; Heart; Hematopoietic; Heterogeneity; Homeobox; Human; Immune; Immune Tolerance; Immunity; Life; Lymphangiogenesis; Lymphatic; Lymphatic Endothelial Cells; Lymphatic Endothelium; Lymphatic function; Maps; Mediating; Modeling; Morphology; Mus; Natural regeneration; Neonatal; Newborn Infant; Organ; Organ Transplantation; Pathway interactions; Phase; Play; Process; Production; Proteomics; Regulatory T-Lymphocyte; Rejuvenation; Reporter; Reporting; Research Design; Research Proposals; Role; Stromal Cells; Structure; T cell differentiation; T-Lymphocyte; T-Lymphocyte Subsets; Technology; Testing; Thymic epithelial cell; Thymus Gland; Time; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factor Receptor-3; Vascular Endothelial Growth Factors; Venous; aged; angiogenesis; cancer therapy; cell type; comparative; emerging adult; improved; in vivo; lymph nodes; lymphatic development; lymphatic vasculature; lymphatic vessel; mouse model; neonatal period; neonate; novel; organ growth; podoplanin; postnatal; primary lymphoid organ; rapid growth; receptor; sex; single-cell RNA sequencing; thymic regeneration; timeline; trafficking; transcription factor; transcriptome; transcriptomics; trend; young adult

PROJECT SUMMARY/ABSTRACT Studies of the thymic microenvironment have focused largely on the central role of thymic epithelial cells (TECs) during development, disease and aging. However recent evidence suggests that the thymic vascular compartment also plays an active and complex role within the thymus beyond that of a simple conduit for hematopoietic cells. This role is particularly evident during the neonatal period when robust thymopoiesis is accompanied by a profound though transient phase of angiogenesis, followed by rapid maturation of TECs. This research proposal builds on the recent and novel finding that the vasculature of the neonatal thymus is in fact dominated by lymphatic endothelial cells (LECs) rather than blood endothelial cells (BECs), the latter becoming dominant by early adulthood. The application of classical LEC-associated cell surface markers is problematic in the thymus in which these markers are either undetectable or expressed on other cell types. The few reports describing the existence of lymphatics in the thymus have studied the adult organ in which LECs are very rare. As a result, the existence of the lymphatic compartment of the thymus has remained largely ignored and the function of LECs and the vasculature they form is unknown. The recent development of key technical advances now allows us to explore this poorly understood cellular compartment of the thymus. Reliable mouse models developed to study LECs in other organs, will now be applied for the first time to identify and manipulate LECs in the thymus. Single cell transcriptomics, including spatial gene expression and proteomics, will allow the detailed simultaneous analysis of LECs, BECs and the other compartments of the thymus during development and after in vivo perturbation of LECs. By combining these powerful technologies, we will test the hypothesis that the lymphatic vasculature of the neonatal period plays a critical role in both the remodeling and maturation of the murine thymic architecture and the differentiation and egress of T cells during the same period. The transcriptional signature of thymic LECs so developed in the mouse will allow direct comparative transcriptional studies of the LECs in the human thymus that would be impossible by standard assays. Specifically, we aim to: 1. Define the lymphatic compartment of the thymus during development at the cellular and transcriptional level 2. Determine if inhibition of lymphangiogenesis affects development of the thymic microenvironment 3. Define the role of lymphangiogenesis in T cell differentiation and egress from the developing thymus In summary we will use the unique window of the murine neonatal period to define the factors that control the growth and regression of the lymphatic endothelium in the thymus, as well as the role of LECs in the dramatic concurrent changes seen in the other thymic compartments. The ultimate goal of these studies is to uncover novel pathways that may be explored for enhancing thymic function and regeneration to improve immunity and health.

项目摘要/摘要 胸腺微环境的研究主要集中在胸腺上皮细胞（TECs）的核心作用 在发育、疾病和衰老的过程中。然而，最近的证据表明， 隔室在胸腺内也起着积极和复杂的作用，超出了一个简单的管道， 造血细胞这一作用在新生儿期尤其明显，此时， 伴随着血管生成的深刻但短暂的阶段，随后是TEC的快速成熟。这 一项研究建议建立在最近的新发现之上，即新生儿胸腺的脉管系统实际上是 主要由淋巴管内皮细胞（LEC）而不是血液内皮细胞（BEC），后者成为 在成年早期占主导地位经典LEC相关细胞表面标志物的应用在以下方面存在问题： 这些标记物在胸腺中检测不到或在其他细胞类型上表达。少数报告 描述胸腺中存在淋巴细胞的人研究了淋巴细胞非常罕见的成年器官。 因此，胸腺淋巴区室的存在在很大程度上仍然被忽视， LEC和它们形成的脉管系统的功能是未知的。关键技术进步的最新发展 现在我们可以探索胸腺的这个知之甚少的细胞区室。可靠的小鼠模型 开发用于研究其他器官中的LEC，现在将首次应用于识别和操纵LEC 在胸腺中。单细胞转录组学，包括空间基因表达和蛋白质组学， 详细的同时分析LEC，BEC和胸腺发育过程中的其他隔室 以及在LEC的体内扰动之后。通过结合这些强大的技术，我们将测试假设 新生儿时期的淋巴管系统在重塑和成熟中起着关键作用， 的小鼠胸腺结构和T细胞的分化和出口在同一时期。的 在小鼠中如此发育的胸腺LEC的转录特征将允许直接比较转录特征。 研究人类胸腺中的淋巴细胞，这是不可能通过标准测定法进行的。具体而言，我们的目标是： 1.在细胞和转录水平上定义发育过程中胸腺的淋巴区室 2.确定抑制淋巴管生成是否影响胸腺微环境的发育 3.明确淋巴管生成在T细胞分化和从发育中的胸腺中排出中的作用 总之，我们将使用小鼠新生期的独特窗口来定义控制小鼠生长的因素。 胸腺淋巴管内皮细胞的生长和消退，以及淋巴管内皮细胞在胸腺淋巴管内皮细胞的生长和消退中的作用。 在其他胸腺隔室中观察到的并发变化。这些研究的最终目的是揭示 可以探索新的途径来增强胸腺功能和再生，以提高免疫力， 健康