Lymphatic-adipocyte interactions in obesity and lymphedema

肥胖和淋巴水肿中的淋巴-脂肪细胞相互作用

• 批准号: 10622592
• 负责人: Gregory Westcott
• 金额: $ 16.45万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10622592
• 关键词: Acceleration; Adipocytes; Adipose tissue; Adult; Affect; Animal Model; Area; Biological; Biology; Body Composition; Body Weight; Body fat; Boston; Breast Cancer Treatment; Cell Communication; Cells; Chronic; Clinical; Collaborations; Complex; Data; Deposition; Desire for food; Development; Disease; Evaluation; Excision; Extracellular Fluid; Fatty acid glycerol esters; Functional disorder; Future; Gene Expression; Gene Expression Profile; Genetic Transcription; Goals; Health; Histologic; Histology; Homeostasis; Hormones; Human; Hypertrophy; Immune; Impairment; Insulin Resistance; Intercellular Fluid; Knockout Mice; Leptin; Leptin resistance; Ligands; Lipedema; Liquid substance; Lymphangiogenesis; Lymphatic; Lymphatic Diseases; Lymphatic Endothelial Cells; Lymphatic System; Lymphatic clearance; Lymphatic function; Lymphedema; Mediating; Mentors; Mentorship; Metabolic; Metabolic dysfunction; Metabolism; Mus; Neurotensin; Obesity; Operative Surgical Procedures; Paracrine Communication; Pathology; Patients; Permeability; Physicians; Physiology; Prevalence; Program Development; Proliferating; Publishing; Regulation; Resolution; Resources; Risk Factors; Role; Scientist; Signal Transduction; System; Techniques; Thermogenesis; Tissue Differentiation; Tissue Expansion; Tissues; Tube; Vascular System; Weight Gain; Work; adipocyte biology; career; career development; cell type; energy balance; experience; human subject; improved; insight; interest; leptin receptor; lymph flow; lymph nodes; lymphatic dysfunction; lymphatic malformations; lymphatic vasculature; lymphatic vessel; mouse model; programs; receptor; single nucleus RNA-sequencing; single-cell RNA sequencing; skills; subcutaneous; trafficking; uptake

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.

项目总结/摘要 脂肪组织的稳态和扩张需要多种细胞类型的协调，以适应 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 淋巴管系统，负责清除细胞外液和免疫细胞 从组织运输到淋巴结。在肥胖症中，脂肪和代谢之间的关系变得 失调，导致淋巴管功能障碍，包括血管形成减少， 渗透性和收缩性降低。相反，在淋巴功能受损的情况下，例如 淋巴结切除后，脂肪组织失调，并在受影响的地方加速扩张。 区 鉴于肥胖及其并发症的日益普遍，以及数百万人的水肿负担， 手术后患者，调节脂肪组织和代谢之间关系的机制， 都很重要广泛地说，这项建议将调查细胞类型的具体相互作用， 关系该实验室的单核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激素， 能量平衡-淋巴功能。初步研究表明，瘦素增加淋巴细胞 管的形成和影响基因表达，本提案的目的1描述了一个计划，以进一步定义瘦素的 淋巴功能的作用。目的2建议从另一个角度研究脂肪细胞-淋巴管的关系 通过对与水肿相关的脂肪组织进行单核RNA测序， 人类受试者，从而揭示细胞组成和转录谱的变化后，破坏 当地的考古学家。 这个为期五年的职业发展计划将建立和扩大候选人的技能和经验， 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 采用许多新技术来评估淋巴管功能。通过组建一个导师团队 和合作者谁是装备精良，以促进这些研究，除了补充教学工作， 该项目将使候选人过渡到一个独立的职业生涯作为一个物理学家，科学家在外地 脂肪组织生物学和新陈代谢的研究。