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

项目摘要/摘要 这项拟议的职业发展奖将为Diana Alba医学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人员，以及 “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 还有糖尿病。在某些个体中，脂肪组织在肥胖中调节失调，这是肥胖的早期调节因素 糖尿病发病机制。然而，这种功能障碍背后的确切原因并未得到明确界定。皮下 白色脂肪组织(SWAT)纤维化与胰岛素抵抗有关，而热量丰富- 在SWAT中产生棕色样脂肪细胞(“褐变”)与代谢健康有关。拟议的研究计划 旨在弥合关于SWAT纤维化和褐化对胰岛素的相互影响的关键知识差距 敏感度。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 不同水平的SWAT纤维化和胰岛素敏感性，并利用这一资源综合探讨 使SWAT摆脱米色影响的关键细胞成分和分子途径 脂肪细胞导致纤维化和胰岛素抵抗。PI的目标是1)识别转录签名 SWAT中协调调节WAT纤维化、体脂分布和血糖的细胞类型 动态平衡，2)探讨SWAT米色活性和纤维化对胰岛素敏感性的交互影响 转录调控，3)以重组近交系小鼠BXD品系作为正交遗传参照系 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 在人类研究中被确认。 拟议的5年职业发展和培训计划纳入了战略性设计的说教 学习、有指导的实践培训和职业建议，以关键的方式补充PI的专业知识 为了完成她的研究和职业目标。本文件中概述的具体职业发展目标 应用包括通过亲身实践的分子在1)脂肪组织生物学方面开发机械专业知识 和计算生物学培训；2)小鼠模型的新陈代谢评估；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- 基础研究和翻译研究的一流中心和良好的医生-科学家培训环境 与拟议培训的所有方面的专家一起进行培训。她将得到专家Suneil Koliwad博士的密切指导 炎症、营养和葡萄糖/能量代谢方面的研究，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独立医生所需的技能，R01- 资助的教职员工致力于确定与脂肪组织疾病相关的机制和风险标记物 糖尿病，特别是在高危人群中，并阐明具体减轻胰岛素抵抗的目标。

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.