Dissecting the cellular interplays of adipose tissue remodeling in the regulation of insulin sensitivity

剖析脂肪组织重塑在胰岛素敏感性调节中的细胞相互作用

• 批准号: 10673921
• 负责人: Diana Lucia Alba
• 金额: $ 16.83万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10673921
• 关键词: Activities of Daily Living; Address; Adipocytes; Adipose tissue; Automobile Driving; Basic Science; Biology; Body Weight; Body fat; Body mass index; CD81 gene; Cell Count; Cell Differentiation process; Cell surface; Clinical; Complement; Computational Biology; Coupled; Data; Dedications; Deterioration; Diabetes Mellitus; Disease; East Asian; Energy Metabolism; Ensure; Environment; Equilibrium; Ethnic Origin; Ethnic Population; Faculty; Fatty acid glycerol esters; Fibrosis; Frequencies; Functional disorder; Funding; GTF2IRD1 gene; Gender; Gene Expression Profile; Genes; Genetic; Genetic Models; Genetic Transcription; Genetic Variation; Glucose; Goals; Growth; Health; Hormones; Human; Hyperplasia; Hypertrophy; Impairment; Inbred Mouse; Inbred Strains Mice; Individual; Inflammation; Insulin Resistance; Intra-abdominal; K-Series Research Career Programs; Knowledge; Learning; Link; Mediator; Mentors; Metabolic; Modeling; Molecular; Molecular Biology; Molecular Probes; Morbidity - disease rate; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Participant; Pathway interactions; Pattern; Persons; Phenotype; Physicians; Population; Process; Production; Race; Recombinants; Research; Research Personnel; Resources; Risk Marker; Role; Scientist; Series; System; Thermogenesis; Time; Tissue Banks; Tissue Expansion; Training; Transcriptional Regulation; Transforming Growth Factor beta; Translational Research; Translations; Visceral; Visceral fat; Vulnerable Populations; Work; bioinformatics tool; blood glucose regulation; career; career development; cell type; clinically relevant; cofactor; cohort; comorbidity; design; diabetes pathogenesis; diabetes risk; falls; genome wide association study; high risk population; human old age (65+); innovation; insulin regulation; insulin sensitivity; interest; lipid biosynthesis; member; metabolic phenotype; mortality; mouse model; multi-ethnic; multiple omics; nutrition; personalized approach; racial diversity; racial population; skills; stem cells; subcutaneous; tool; transcriptome

PROJECT SUMMARY/ABSTRACT This proposed career development award will provide Dr. Diana Alba MD with targeted mentored training to ensure she develops into an independent researcher utilizing both experimental approaches and models, and “omics” coupled with bioinformatic tools, to probe the mechanisms linking obesity to adipose tissue dysfunction and diabetes. In certain individuals, adipose tissue is dysregulated in obesity, and this is an early mediator of diabetes pathogenesis. However, precisely what underlies this dysfunction is not well-defined. Subcutaneous white adipose tissue (sWAT) fibrosis is associated with insulin resistance, whereas the abundance of heat- generating brown-like adipocytes in sWAT (“beiging”) is linked to metabolic health. The proposed research plan aims to close key knowledge gaps regarding the reciprocal influences of sWAT fibrosis and beiging on insulin sensitivity. To do so, the PI will take advantage of an innovative human cohort containing individuals with widely divergent levels of both sWAT fibrosis and insulin sensitivity and use this resource to comprehensively probe key cellular constituents and molecular pathways that shift sWAT away from being influenced by beige adipocytes to developing fibrosis and insulin resistance. The PI aims to 1) identify transcriptional signatures across cell types in the sWAT that coordinately modulate WAT fibrosis, body fat distribution, and glucose homeostasis, 2) probe reciprocal influences of sWAT beige activity and fibrosis on insulin sensitivity via transcriptional regulation, 3 ) use the BXD panel of recombinant inbred mice as an orthogonal genetic reference to model divergent patterns of fat distribution and validate the mechanistic relevance of pathways and cell types identified in the humans studies. The proposed 5-year career development and training plan incorporates strategically designed didactic learning, mentored practical training, and career advising to complement the PI’s expertise in ways that are critical to completion of her research and career goals. The specific career development goals outlined in this application include developing mechanistic expertise in 1) adipose tissue biology through hands-on molecular and computational biology training; 2) metabolic assessment of mouse models; 3) the human translation of adipose tissue biology including multi-omics and metabolic phenotyping. She will be training at UCSF, a world- class center for basic and translational research and an excellent environment for physician-scientist training with experts in all aspects of the proposed training. She will be closely mentored by Dr. Suneil Koliwad, an expert in inflammation, nutrition, and glucose/energy metabolism, and Dr. Shingo Kajimura, an expert in adipogenesis and beige fat. The long-term goal is to provide Dr. Alba with the skills required to become an independent, R01- funded faculty member working to identify adipose tissue disease-relevant mechanisms and risk markers for diabetes, particularly in high-risk populations, and elucidate targets to specifically mitigate insulin resistance.

项目总结/摘要 这项拟议的职业发展奖将为Diana Alba博士提供有针对性的指导培训 确保她发展成为一个独立的研究人员利用实验方法和模型， “组学”结合生物信息学工具，探索肥胖与脂肪组织功能障碍的联系机制 和糖尿病在某些个体中，脂肪组织在肥胖中失调，这是肥胖的早期介导者。 糖尿病发病机制然而，这种功能障碍的确切原因并没有得到很好的界定。皮下 白色脂肪组织（sWAT）纤维化与胰岛素抵抗相关，而大量的热- 在sWAT（“beiging”）中产生棕色样脂肪细胞与代谢健康有关。拟议的研究计划 旨在填补关于sWAT纤维化和beiging对胰岛素的相互影响的关键知识空白 灵敏度为了做到这一点，PI将利用一个创新的人类队列，其中包含具有广泛免疫缺陷的个体。 sWAT纤维化和胰岛素敏感性的不同水平，并使用此资源全面探索 使sWAT免受米色影响的关键细胞成分和分子途径 脂肪细胞发展纤维化和胰岛素抵抗。PI的目标是1）识别转录特征 协调调节WAT纤维化、体脂分布和葡萄糖的sWAT中的细胞类型 稳态，2）通过以下途径探测sWAT米色活性和纤维化对胰岛素敏感性的相互影响： 转录调控，3）使用重组近交系小鼠的BXD板作为正交遗传参考 模拟脂肪分布的不同模式，并验证途径和细胞类型的机械相关性， 在人类研究中发现。 拟议的5年职业发展和培训计划纳入了战略性设计的教学 学习，指导实践培训和职业咨询，以补充PI的专业知识的方式是至关重要的 完成她的研究和职业目标。本报告中概述的具体职业发展目标 应用包括：1）通过实际操作的分子生物学， 和计算生物学训练; 2）小鼠模型的代谢评估; 3）人类翻译 脂肪组织生物学，包括多组学和代谢表型。她将在加州大学旧金山分校接受训练，一个世界- 一流的基础和转化研究中心和良好的环境，为医生，科学家的培训 与拟议培训的各个方面的专家进行合作。她将得到专家Suneil Koliwad博士的密切指导 炎症、营养和葡萄糖/能量代谢方面的专家，以及脂肪生成专家Shingo Kajimura博士 和米色脂肪长期目标是为阿尔巴博士提供成为一名独立的R 01- 受资助的教员致力于确定脂肪组织疾病相关机制和风险标志物， 糖尿病，特别是在高风险人群中，并阐明具体减轻胰岛素抵抗的目标。