权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

The role of vascular endothelium in BAT expansion and remodeling

血管内皮在 BAT 扩张和重塑中的作用

基本信息

批准号：
10888081
负责人：
Farnaz Shamsi
金额：
$ 3.83万
依托单位：
NEW YORK UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10888081
关键词：
Address Adipocytes Adipose tissue Adult Biological Assay Biology Blood Vessels Brown Fat Cardiovascular Diseases Cell Line Cell Proliferation Communication Culture Media Data Development Diabetes Mellitus Diet Endothelial Cells Endothelium Energy Metabolism Environment Etiology Exposure to Fatty Acids Fatty acid glycerol esters Flow Cytometry Gene Delivery Gene Expression Genes Goals Health High Fat Diet Homeostasis Housing Human Impairment In Situ In Vitro Inflammation Investigation K-Series Research Career Programs Knowledge Ligands Link Measures Mediating Mediator Mentors Mesenchymal Stem Cells Metabolic Metabolic Diseases Mitochondria Modeling Molecular Mouse Strains Mus Non-Insulin-Dependent Diabetes Mellitus Nutritional Nutritional status Obese Mice Obesity Obesity Epidemic Pathway interactions Play Population Positioning Attribute Prevalence Proliferating Recombinant Proteins Regulation Reporter Research Research Personnel Role Series Site Source Stimulus Temperature Testing Therapeutic Thermogenesis Tissue Expansion Tissues Training Triglycerides Vascular Endothelium Vascular remodeling Visualization Weight Gain Western Blotting angiogenesis career development cell motility cell type cold temperature combat comorbidity density diet-induced obesity dietary control environmental change experimental study feeding global health glucose metabolism glucose tolerance in vivo insulin sensitivity intercellular communication lipid biosynthesis multidisciplinary novel novel therapeutic intervention obesity treatment overexpression prevent progenitor programs protein expression receptor recruit response single-cell RNA sequencing skill acquisition stem cells training opportunity transcriptome sequencing uncoupling protein 1 warm temperature

项目摘要

Project Summary/Abstract The rising prevalence of obesity and its comorbidities is a major global health concern. The development of strategies to prevent or treat human obesity is therefore of the utmost importance. Brown adipose tissue (BAT) and its related beige fat are specialized for energy expenditure. The identification of metabolically active brown and beige fat in adult humans has positioned this tissue at the center of investigations into human energy metabolism. Considering the formidable capacity of BAT for energy expenditure and its role in fatty acid and glucose metabolism, strategies leading to increased mass or enhanced activity of BAT can potentially be utilized to combat obesity and its related metabolic disorders. Different adipose depots undergo massive remodeling in response to environmental stimuli, such as cold and diet. Prolonged cold exposure leads to recruitment of new brown adipocytes as well as a coordinated expansion and remodeling of vascular endothelium in classical BAT to enable maximal thermogenic capacity. However, the cellular origin of the cold-induced brown adipocytes, and the identity of intracellular communication pathways coordinating the adipogenesis and angiogenesis are not known. The overall goal of this proposal is to identify the role of endothelial cells in BAT expansion and remodeling in response to cold exposure and high fat diet. To address this, we used single cell RNA-sequencing (scRNA-seq) to uncover the temperature-dependent remodeling of each cell type within BAT. The preliminary data have made the novel discovery that cold exposure triggers the induction of brown adipocyte thermogenic program in endothelial cells (ECs). Additionally, the cell-type specific gene expression data allowed the identification of a Slit3-Robo4 as a potential ligand-receptor interaction mediating the crosstalk between adipocyte progenitors and ECs. The central hypotheses are that ECs contribute to cold-induced BAT expansion through de novo differentiation to thermogenic adipocytes and that Slit3 secretion from adipocyte progenitors promotes EC proliferation and angiogenesis through interaction with EC Robo4 receptor. This proposal will determine the contribution of ECs to thermogenic adipocytes pool (Aim 1) and will address the role of Slit3- Robo4 interaction in regulating adipose tissue remodeling and angiogenesis in response to high fat feeding (Aim 2). Successful completion of this proposal will change the current premise and will establish novel molecular players linking adipogenesis and angiogenesis and will have profound biomedical implications. The mentored career development award will be used to achieve a series of training objectives including expanding applicant’s knowledge in vascular biology and professional development skills that are essential for transition to an independent investigator. The training plan will build upon applicant’s expertise in adipose tissue biology and will enable the establishment of a unique cutting-edge research program in obesity and diabetes field. The team of mentors and collaborators will provide an integrative and multidisciplinary training opportunity for the applicant to receive intellectual and technical support and career development advice.

项目摘要/摘要肥胖症及其合并症的患病率不断上升，是一个重大的全球健康问题。的发展。因此，预防或治疗人类肥胖的战略至关重要。棕色脂肪组织(BAT) 和它相关的米色脂肪是专门用于能量消耗的。具有代谢活性的棕色物质的鉴定成年人体内的米色脂肪将这种组织置于人体能量研究的中心新陈代谢。考虑到BAT强大的能量消耗能力及其在脂肪酸和葡萄糖代谢，导致蝙蝠质量增加或活动增强的策略可能被利用与肥胖及其相关代谢紊乱作斗争。不同的脂肪库经历了大规模的改建对环境刺激的反应，如感冒和饮食。长期的寒冷暴露导致招募新的经典蝙蝠棕色脂肪细胞与血管内皮细胞的协调扩张和重塑以实现最大的生热能力。然而，冷诱导的棕色脂肪细胞的细胞来源，以及协调脂肪生成和血管生成的细胞内通讯通路的同一性尚不清楚为人所知。这项提案的总体目标是确定内皮细胞在BAT扩张和冷暴露和高脂饮食所致的重构。为了解决这个问题，我们使用了单细胞RNA测序 (scRNA-seq)，以揭示BAT内每种细胞类型的温度依赖性重塑。预赛数据已经有了新的发现，冷暴露会触发棕色脂肪细胞产热的诱导在内皮细胞(ECs)中进行编程。此外，细胞类型特定的基因表达数据允许 SLIT3-Robo4作为一种潜在的配体-受体相互作用的鉴定脂肪细胞前体细胞和内皮细胞。中心假设是内皮细胞促进了冷诱导的BAT扩张。通过从头向生热脂肪细胞分化以及脂肪细胞祖细胞分泌SLIT3 通过与EC Robo4受体的相互作用促进EC的增殖和血管生成。这项提议将确定内皮细胞对生热脂肪细胞池的贡献(目标1)，并将讨论SLIT3- Robo4相互作用在调节高脂饮食下脂肪组织重塑和血管生成中的作用 2)。这一方案的成功完成将改变目前的前提，并将建立新的分子将脂肪生成和血管生成联系起来的参与者将具有深远的生物医学意义。被指导者职业发展奖将用于实现一系列培训目标，包括扩大申请者的血管生物学知识和专业发展技能是过渡到独立调查员。培训计划将以申请者在脂肪组织生物学方面的专业知识为基础，并将在肥胖和糖尿病领域建立独一无二的前沿研究计划。这支队伍导师和合作者将为申请者提供综合和多学科的培训机会接受智力和技术支持以及职业发展建议。