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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要拟议的职业发展奖将为医学博士戴安娜·阿尔巴博士提供有针对性的指导培训确保她发展成为一名利用实验方法和模型的独立研究员，并且 “组学”与生物信息工具相结合，探讨肥胖与脂肪组织功能障碍之间的联系机制在某些个体中，脂肪组织在肥胖症中失调，这是肥胖的早期介质。然而，这种皮下功能障碍的确切原因尚不清楚。白色脂肪组织（SWAT）纤维化与胰岛素抵抗有关，而大量的热- 拟议的研究计划在 swat（“beiging”）中产生棕色样脂肪细胞与代谢健康有关。旨在弥合有关 SWAT 纤维化和开始使用胰岛素的相互影响的关键知识差距为此，PI 将利用一个包含具有广泛敏感性的个体的创新人类队列。 SWAT 纤维化和胰岛素敏感性的不同水平，并使用此资源来全面探测使 SWAT 免受米色影响的关键细胞成分和分子途径脂肪细胞纤维化和胰岛素抵抗的目的是 1) 识别转录特征。协调调节 WAT 纤维化、身体脂肪分布和葡萄糖的 SWAT 中的跨细胞类型稳态，2) 通过以下方式探究 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）使用重组近交小鼠的BXD panel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制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包含战略设计的教学学习、指导实践培训和职业建议，以关键方式补充 PI 的专业知识完成她的研究和职业目标。通过动手分子实践开发 1) 脂肪组织生物学方面的应用机械专业知识和计算生物学训练；2）小鼠模型的代谢评估；3）人类翻译她将在 UCSF 接受培训，包括多组学和代谢表型分析。基础和转化研究的一流中心以及医师科学家培训的优良环境她将得到专家 Suneil Koliwad 博士的密切指导。炎症、营养和葡萄糖/能量代谢领域的研究专家，以及脂肪生成专家 Shingo Kajimura 博士和米色脂肪的长期目标是为阿尔巴博士提供成为独立人士所需的技能，R01- 资助的教职人员致力于确定脂肪组织疾病相关机制和风险标记糖尿病，特别是高危人群，并阐明专门减轻胰岛素抵抗的目标。