The Role of Mitochondrial TNAP in Adaptive Thermogenesis

线粒体 TNAP 在适应性产热中的作用

• 批准号: 10591696
• 负责人: Yizhi Sun
• 金额: $ 12.9万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10591696
• 关键词: Ablation; Acceleration; Address; Adipocytes; Adipose tissue; Advisory Committees; Alkaline Phosphatase; Amino Acid Sequence; Animals; Area; Automobile Driving; Binding Proteins; Biochemical; Biological; Biology; Biophysics; Cardiovascular Diseases; Cells; Chemicals; Consumption; Creatine; Cysteine; Dana-Farber Cancer Institute; Data; Diabetes Mellitus; Disease; Doctor of Philosophy; Elements; Energy Metabolism; Ensure; Environment; Event; Fatty Liver; Fatty acid glycerol esters; Futile Cycling; Generations; Genes; Genetic; Goals; Hydrolysis; Immunoprecipitation; Kidney Diseases; Laboratories; Laboratory Research; Link; Malignant Neoplasms; Mediator; Medical; Membrane Microdomains; Metabolic; Metabolic Diseases; Metabolism; Methods; Mitochondria; Mitochondrial Proteins; Molecular; Mouse Strains; Mus; Muscle Fibers; Mutation Analysis; Obesity; Oxidative Phosphorylation; Pathway interactions; Phosphocreatine; Phosphorylation; Physiological; Play; Post-Translational Protein Processing; Prevention; Process; Protein Dephosphorylation; Proteins; Proteome; Proteomics; Public Health; Reactive Oxygen Species; Regulation; Reporter; Research; Research Personnel; Respiration; Role; Signal Transduction; Specificity; Testing; Therapeutic; Thermogenesis; Tissue Engineering; Tissues; Transgenic Mice; Transportation; Travel; Variant; Visualization; Work; adipocyte biology; career; cellular imaging; diet-induced obesity; gain of function; genetic approach; imaging approach; imaging study; innovation; medical schools; metabolic abnormality assessment; novel; obesity prevention; obesity treatment; operation; pharmacologic; polypeptide; protein transport; red fluorescent protein; therapeutic target; trafficking

Abstract Thermogenic adipocytes and adaptive thermogenesis are promising therapeutic targets for treating and preventing obesity and obesity-linked diabetes. We recently demonstrated that the mitochondrial tissue- nonspecific alkaline phosphatase, TNAP, plays a crucial role in the futile creatine cycle (FCC) and adaptive thermogenesis by hydrolyzing phosphocreatine. Pharmacological inhibition or genetic ablation of TNAP in mice reduces systemic energy expenditure. Genetic ablation of TNAP in mice also causes rapid-onset obesity. TNAP assumes a mitochondrial localization specifically in thermogenic adipocytes, which might ensure the cell- selectivity of the phosphocreatine hydrolysis events and the FCC operation. Here, we propose to study the metabolic effects of gain-of- function of TNAP in the adipose tissues in mice, as well as the molecular mechanism and regulation of its mitochondrial localization. Using a transgenic mouse strain that artificially expresses TNAP in the adipose tissues, we will investigate its effects on obesity, diabetes, fatty liver, and energy expenditure. To study the TNAP localization, we will test whether its cell specificity lies in the TNAP polypeptide or its trafficking pathway, or both. I will first determine whether there are any molecular elements (e.g., PTMs or amino acid sequences) on the TNAP polypeptide crucial for its mitochondrial localization. This will be done using a combination of biochemical and cell imaging approaches. In addition, we will investigate the cellular pathway of TNAP trafficking to mitochondria. We will interrogate the role of lipid rafts in TNAP localization. This might allow us to identify key regulators and mediators of the mitochondrial localization of TNAP. Finally, we will identify other mitochondrial proteins that share the localization pathway of TNAP and study their functions. The candidate, Dr. Yizhi Sun, has a strong track record of innovative research with a focus on the molecular mechanisms of diseases. The candidate’s career goal is to become an independent academic investigator with a research laboratory oriented towards understanding and reversing obesity and obesity-linked metabolic disorders. The proposed research will be conducted in the laboratory of Bruce Spiegelman, PhD at Dana-Farber Cancer Institute and Harvard Medical School, who is a leader in the fields of molecular metabolism and adipocyte biology. The proposed studies will also bring together leading laboratories of the advisory committee that have expertise in cell imaging, protein trafficking, and mitochondrial biology. All of these, together with the ideal research environment in the Longwood Medical Area, will maximize applicant’s potential to successfully transition to an independent investigator.

抽象的 热脂肪细胞和自适应热发生是治疗和 预防肥胖和肥胖连接糖尿病。我们最近证明了线粒体组织 非特异性酒精磷酸酶TNAP在徒劳的肌酸周期（FCC）和自适应中起着至关重要的作用 通过水解磷酸蛋白的热生成。小鼠TNAP的药理抑制或遗传消融 减少系统性能量消耗。小鼠TNAP的遗传消融也会引起快速发作的肥胖症。 TNAP 假设在热脂肪细胞中专门用于线粒体定位，这可以确保细胞 磷酸盐水解事件和FCC操作的选择性。在这里，我们建议研究 TNAP在小鼠脂肪组织中的代谢作用以及分子机制 并调节其线粒体定位。使用人为表达TNAP的转基因小鼠菌株 在脂肪组织中，我们将研究其对肥胖，糖尿病，脂肪肝和能量消耗的影响。到 研究TNAP定位，我们将测试其细胞特异性是否在于TNAP多肽还是贩运 路径，或两者兼而有之。我将首先确定是否有任何分子元素（例如PTMS或氨基酸 序列）在TNAP多肽对线粒体定位至关重要的情况下。这将使用 生化和细胞成像方法的组合。此外，我们将研究 TNAP贩运线粒体。我们将询问脂质筏在TNAP定位中的作用。这可能允许 美国确定TNAP线粒体定位的关键调节剂和介体。最后，我们将确定 其他线粒体蛋白共享TNAP的定位途径并研究其功能。 候选人Yizhi Sun博士拥有创新研究的良好记录，重点是分子 疾病的机制。候选人的职业目标是成为独立的学术研究员 一个研究实验室，旨在理解和逆转肥胖和与肥胖相关的代谢 疾病。拟议的研究将在Dana-Farber博士的Bruce Spiegelman实验室进行 癌症研究所和哈佛医学院，他是分子代谢和脂肪细胞领域的领导者 生物学。拟议的研究还将汇集咨询委员会的领先实验室 细胞成像，蛋白质运输和线粒体生物学方面的专业知识。所有这些，以及理想 朗伍德医疗区的研究环境将最大化申请人成功的潜力 过渡到独立研究者。