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: 10426706
• 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/10426706
• 关键词: Adipocytes; Adipose tissue; Adult; Affect; Animal Model; Area; Biological; Biology; Body Composition; Body Weight; Body fat; Boston; Breast; Cell Communication; Cell Nucleus; 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; Obesity; Operative Surgical Procedures; Paracrine Communication; Pathology; Patients; Permeability; Physicians; Physiology; Prevalence; Program Development; 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-cell RNA sequencing; skills; subcutaneous; trafficking; transcriptome sequencing; 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.

项目摘要/摘要 脂肪组织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。脂肪组织调节的重要组成部分是 淋巴血管系统，负责去除细胞外液和免疫细胞 从组织到淋巴结的运输。在目标上，脂肪和淋巴管之间的关系变成 失调，导致淋巴血管功能障碍，包括血管形成减少，增加 渗透性和收缩性降低。相反，在淋巴功能受损的条件下，例如 淋巴结切除，脂肪组织失调，经历了受影响的加速膨胀 区域。 鉴于肥胖症及其并发症的患病率越来越高，以及数百万的淋巴水肿的燃烧 术后患者，调节脂肪组织与淋巴管之间关系的机制 具有重大兴趣。从广义上讲，该提案将调查控制这一点的细胞类型特定相互作用 关系。实验室的单核RNA测序数据表明淋巴内皮细胞表达 瘦素受体，表明瘦素的作用 - 脂肪细胞产生的马酮，可调节有机体 能量平衡 - 淋巴功能。初步研究表明，瘦素增强淋巴管 试管形成并影响基因表达，目的1的目的描述了进一步定义瘦素的计划 在淋巴功能中的作用。目标2从替代方案研究脂肪细胞淋巴关系的建议 通过在与淋巴水肿相关的脂肪组织上进行单核RNA测序 人类受试者，从而揭示了破坏后细胞组成和转录曲线的变化 局部淋巴管。 这个五年的职业发展计划将在候选人的技能和经验中建立并扩大 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，同时也 采用多种新技术评估淋巴管功能。通过组建一个心态团队 除了补充教学工作外，还具有良好能力促进这些研究的合作者 该项目将使候选人过渡到该领域的身体科学家独立职业 脂肪组织生物学和代谢。