Lymphatic-adipocyte interactions in obesity and lymphedema

项目摘要/摘要 脂肪组织的动态平衡和扩张需要多种细胞类型的协调来适应 组织体积和代谢需求的增加。脂肪组织调节的一个重要组成部分是 负责清除细胞外液和免疫细胞的淋巴管系统 从组织到淋巴结的运输。在肥胖中，脂肪和淋巴管之间的关系变成 调节失调，导致淋巴管功能障碍，包括血管形成减少，增加 渗透性和收缩能力减弱。相反，在淋巴功能受损的情况下，如在 淋巴结切除，脂肪组织调节失调，受累患者经历加速扩张 区域。 鉴于肥胖症及其并发症的日益普遍，以及数百万人的淋巴水肿负担 术后患者脂肪组织和淋巴管关系的调节机制 是非常有意义的。广泛地说，这项提案将研究支配这一现象的细胞类型的特定相互作用。 两性关系。实验室的单核RNA测序数据显示，淋巴管内皮细胞表达 瘦素受体，表明瘦素的作用--瘦素是一种脂肪细胞产生的荷尔蒙，调节机体 能量平衡-淋巴功能。初步研究表明，瘦素可以增强淋巴管 管子的形成和对基因表达的影响，本提案的目标1描述了进一步定义瘦素的计划 在淋巴功能中的作用。目的2建议从另一种角度研究脂肪细胞与淋巴的关系 通过对与淋巴水肿相关的脂肪组织进行单核RNA测序来指导 人类受试者，从而揭示细胞组成和转录图谱在干扰后的变化 当地的淋巴管。 这项为期五年的职业发展计划将建立和扩大候选人在以下领域的技能和经验 研究脂肪细胞生物学、代谢功能障碍的动物模型和单细胞RNA测序，同时还 使用许多新技术来评估淋巴管功能。通过组建一个导师团队 以及有能力促进这些研究的合作者，除了辅助教学工作外， 该项目将使候选人能够过渡到独立的职业生涯，成为一名领域内的内科科学家 脂肪组织生物学和新陈代谢的研究。

Project Summary/Abstract Adipose tissue homeostasis and expansion requires the coordination of multiple cell types to accommodate increases in tissue volume and metabolic requirements. An important component of adipose tissue regulation is the lymphatic vascular system, which is responsible for the removal of extracellular fluid and for immune cell trafficking from the tissue to lymph nodes. In obesity, the relationship between fat and lymphatics becomes dysregulated, resulting in lymphatic vessel dysfunction, including decreased vessel formation, increased permeability, and diminished contractility. Conversely, in conditions of impaired lymphatic function, such as after lymph node resection, adipose tissue is dysregulated and experiences accelerated expansion in the affected area. Given the increasing prevalence of obesity and its complications, as well as the burden of lymphedema in millions of post-surgical patients, the mechanisms which regulate the relationship between adipose tissue and lymphatics are of significant interest. Broadly, this proposal will investigate cell-type specific interactions which govern this relationship. The lab’s single-nucleus RNA sequencing data revealed that lymphatic endothelial cells express the leptin receptor, indicating a role for leptin—an adipocyte-produced hormone which regulates organismal energy balance—in lymphatic function. Preliminary studies have demonstrated that leptin augments lymphatic tube formation and impacts gene expression, and Aim 1 of this proposal describes a plan to further define leptin’s role in lymphatic function. Aim 2 proposes to study the adipocyte-lymphatic relationship from an alternative direction by performing single-nucleus RNA sequencing on adipose tissue associated with lymphedema in human subjects, thereby revealing changes in cellular composition and transcriptional profiles after disruption of local lymphatics. This five-year career development program will build on and expand the candidate’s skills and experience in studying adipocyte biology, animal models of metabolic dysfunction, and single-cell RNA sequencing, while also employing a number of new techniques to evaluate lymphatic vessel function. By assembling a mentorship team and collaborators who are well-equipped to facilitate these studies, in addition to supplementary didactic work, this project will enable the candidate’s transition to an independent career as a physician-scientist in the fields of adipose tissue biology and metabolism.