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.

项目摘要/摘要 该拟议的职业发展奖将为戴安娜·阿尔巴（Diana Alba）博士提供针对性的修订培训 为了确保她利用实验方法和模型以及 加上生物信息学工具的“ OMICS”，以探测将肥胖与脂肪组织功能障碍联系起来的机制 和糖尿病。在某些人中，肥胖症中脂肪组织失调，这是 糖尿病发病机理。但是，正是这种功能障碍的基础不是明确的。皮下 白色脂肪组织（SWAT）纤维化与胰岛素抵抗有关，而热量的抽象 在特警中产生类似棕色的脂肪细胞（“存在”）与代谢健康有关。拟议的研究计划 旨在弥合有关特警纤维化的相互影响并成为胰岛素的关键知识差距 灵敏度。为此，PI将利用一个创新的人类队列，其中包含广泛的人 特警纤维化和胰岛素敏感性的分歧水平，并使用此资源全面证明 关键细胞构成和分子途径，使特警从受米色影响的影响转移 脂肪细胞发展为纤维化和胰岛素抵抗。 PI的目的是1）确定转录签名 在特警中跨越协调调节WAT纤维化，人体脂肪分布和葡萄糖的细胞类型 稳态，2）SWAT米色活性和纤维化对胰岛素敏感性的探针相互影响 转录调节，3）使用重组近交小鼠的BXD面板作为正交遗传参考 建模脂肪分布的发散模式并验证途径和细胞类型的机理相关性 在人类研究中确定。 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，指导实用培训和职业咨询，以至关重要的方式完成PI的专业知识 完成她的研究和职业目标。其中概述了特定的职业发展目标 应用包括在1）通过动手分子来开发机械专业知识 和计算生物学培训； 2）小鼠模型的代谢评估； 3）人类的翻译 脂肪组织生物学，包括多词和代谢表型。她将在UCSF进行培训，这是一个世界 - 基础研究和翻译研究中心以及身体科学家培训的绝佳环境 在拟议培训的各个方面都有专家。她将由专家Suneil Koliwad博士密切处理 在炎症，营养和葡萄糖/能量代谢中，以及脂肪形成专家Shingo Kajimura博士 和米色脂肪。长期目标是向Alba博士提供成为独立的R01-所需的技能。 资助的教职员工努力确定脂肪组织疾病与疾病相关的机制和风险标志 糖尿病，尤其是在高风险人群中，并阐明靶标，以特别减轻胰岛素抵抗。