Development and validation of a human brown adipocyte system

人类棕色脂肪细胞系统的开发和验证

• 批准号: 8904122
• 负责人: YOLANDA Renee LEA-CURRIE
• 金额: $ 22.43万
• 依托单位: ZEN-BIO, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8904122
• 关键词: Address; Adipocytes; Adipose tissue; Adult; Affect; Age; Benchmarking; Biological Assay; Biological Markers; Biological Models; Biology; Body Weight decreased; Brown Fat; Burn injury; Cell Culture System; Cell Line; Cell model; Cells; Communities; Comorbidity; Data; Development; Disease; Drug Targeting; Energy Metabolism; Epidemic; Feasibility Studies; Fetal Tissues; Gender; Generations; Genetic; Goals; Heating; Human; Human Identifications; Incidence; Infant; Knowledge; Lead; Location; Longevity; Measures; Mediating; Metabolic; Metabolic Diseases; Mitochondria; Modality; Modeling; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obesity associated disease; Oxidative Phosphorylation; Pathway interactions; Performance; Phase; Plasma; Population; Prevalence; Procedures; Production; Protocols documentation; Provider; Quality Control; Research; Research Personnel; Respiration; Rodent; Rodent Model; Stimulus; System; Targeted Research; Testing; Therapeutic; Thermogenesis; Tissues; Triglycerides; United States; Validation; adipocyte differentiation; comparative; demographics; diabetic; experience; fatty acid oxidation; fetal; fight against; functional genomics; high throughput screening; immortalized cell; lipid biosynthesis; novel; novel therapeutic intervention; novel therapeutics; obesity treatment; oxidation; phase 1 study; public health relevance; screening; therapeutic target; tool

 DESCRIPTION (provided by applicant): The activation and recruitment of brown adipose tissue has become an exciting target in the fight against obesity and its related metabolic diseases. Brown adipose tissue differs from white adipose tissue in its critical ability to burn energy as heat through UCP-1 driven adaptive thermogenesis. Expression of mitochondrial UCP-1 uncouples oxidative phosphorylation, resulting in accelerated substrate oxidation but low ATP production. The resulting dissipation of energy is associated with plasma triglyceride clearance, a key factor in weight loss. The brown adipose depot has long been known to exist in rodents as well as in human infants. However, recent evidence has demonstrated the existence of active brown adipose tissue in human adults. These findings prompted a resurgence of research focusing on both the activation of brown adipose tissue and the "browning" of white adipose tissue, a phenomenon wherein UCP-1-mediated mitochondrial uncoupling is induced by stimuli. Studies using rodent models have demonstrated that brown fat activation or induction of browning can promote beneficial metabolic effects, and promising therapeutic targets have been identified. However, the therapeutic potential of these targets has not been confirmed due to the lack of a widely available human brown adipocyte model. Therefore, there is a pronounced need to validate existing therapeutic targets in the human system. ZenBio will address this need by providing both a primary and immortalized human brown adipocyte cell culture system to the research community and will utilize these tools to establish a screen to identify activators of human brown adipogenesis. The principal goal of this project is to generate and characterize a human adult brown adipocyte cell system. We will achieve this in a stepwise fashion, beginning with an initial feasibility study focused on human fetal brown adipocytes. Aim I will use functional and genomic analyses to generate a widely available fetal brown adipocyte model which will be used as a tool to establish the adult cell system. The fetal model will be developed first due to the comparative ease of detecting fetal brown adipose tissue and its ready availability through existing procurement agencies. The second aim is to generate and characterize an immortalized fetal brown adipocyte system for high throughput/high content screening. These cells will circumvent the limited material and lifespan of primary cells and allow for the development of a high throughput screening platform to identify novel targets of brown adipocyte activation. Phase I will be expanded in Phase II with the goal of characterizing and commercializing the human adult brown adipocyte system from donors of differing BMI, age, gender and diabetic state. These studies will generate both primary and immortalized human adult adipocyte cells which will be used to identify novel targets of brown adipocyte energy expenditure for the treatment of obesity.

 描述（由申请人提供）：棕色脂肪组织的激活和募集已成为对抗肥胖及其相关代谢疾病的令人兴奋的目标。棕色脂肪组织与白色脂肪组织的不同之处在于其通过 UCP 将能量燃烧为热量的关键能力。 -1 驱动适应性生热作用。线粒体 UCP-1 的表达解偶联氧化磷酸化，导致底物氧化加速，但 ATP 产生较低，从而导致能量耗散。血浆甘油三酯清除率是减肥的关键因素，长期以来人们都知道棕色脂肪库存在于啮齿类动物和人类婴儿中，但最近的证据表明，成年人体内也存在活跃的棕色脂肪组织。关注棕色脂肪组织激活和白色脂肪组织“褐变”的研究重新兴起，这种现象导致 UCP-1 介导的线粒体解偶联，是由啮齿动物模型的刺激引起的。已经证明，棕色脂肪的激活或诱导褐变可以促进有益的代谢作用，并且已经确定了有希望的治疗靶标，但是，由于缺乏广泛可用的人类棕色脂肪细胞模型，这些靶标的治疗潜力尚未得到证实。迫切需要验证人体系统中的现有治疗靶点，ZenBio 将通过向研究界提供原代和永生化人类棕色脂肪细胞培养系统来满足这一需求，并将利用这些工具建立筛选来识别激活剂。人类棕色脂肪生成。该项目的主要目标是生成并表征人类成人棕色脂肪细胞系统，我们将从针对人类胎儿棕色脂肪细胞的初步可行性研究开始，逐步实现这一目标。广泛使用的胎儿棕色脂肪细胞模型将被用作建立成人细胞系统的工具，因为检测胎儿棕色脂肪细胞组织相对容易并且可以通过现有采购机构获得。目的是生成并表征用于高通量/高内涵筛选的永生化胎儿棕色脂肪细胞系统将规避原代细胞的有限材料和寿命，并允许开发高通量筛选平台来识别棕色脂肪细胞激活的新靶点。第二阶段的目标是对来自不同体重指数、年龄、性别和糖尿病状态的捐赠者的成人棕色脂肪细胞系统进行表征和商业化，这些研究将产生原代和永生化的成人脂肪细胞，用于鉴定。棕色脂肪细胞能量消耗治疗肥胖的新目标。