Regulation of fatty acid oxidation in adipose tissues

描述(由申请人提供)： 这份提案详细介绍了一项为期3年的培训计划，以培养候选人埃里克·戈茨曼成为独立研究科学家所需的技能。2006年7月，戈茨曼博士在匹兹堡大学担任助理教授一职，有90%的时间用于发展他的研究事业。他的科学背景是研究酰基辅酶A脱氢酶(ACADS)，这是线粒体脂肪酸氧化酶的一个关键家族。戈茨曼博士现在希望将他关于脂肪酸氧化的知识转移到肥胖和脂肪组织生物学的研究中。生化遗传学家、研究脂肪酸氧化先天错误的专家曾傑瑞·沃克利博士将指导戈茨曼博士的职业培训。罗伯特·奥多尔蒂博士将担任共同赞助人。奥多尔蒂博士是一名肥胖/糖尿病研究人员，也是胰岛素和瘦素信号传递方面的专家。他的指导将为申请者提供新方法方面的培训，并在使用动物模型进行肥胖研究领域提供指导。Goetzman博士提出了三项关键的初步数据：1)脂肪酸氧化减少的基因敲除小鼠脂肪组织中的脂肪酸释放受到失调；2)胰岛素增敏药物罗格列酮增加了特定于脂肪组织的脂肪酸氧化酶的表达和活性；3)脂肪酸氧化酶受到可逆乙酰化的影响，这可能调节脂肪组织的活性。提出了三个具体目标，以调查初步数据提出的问题。目标1将使用基因敲除小鼠和体外技术来确定脂肪酸氧化作为脂肪组织能量来源的重要性。目的2将验证罗格列酮激活一个信号级联导致磷酸化诱导的激活的假说 转录因子PPARpha，进而增加脂肪酸氧化酶的表达。目的3研究酶乙酰化对脂肪组织线粒体脂肪酸氧化速率的影响。此外，将使用纯重组酶来研究乙酰化调节活性的机制。了解脂肪组织中脂肪酸氧化酶的调节对于开发新的减肥疗法非常重要，这种疗法可以将脂肪细胞从脂肪储存转变为更具分解代谢的表型。匹兹堡大学是一个理想的环境，因为强大的研究环境和优秀的导师和顾问的可用性。这种结合将最大限度地发挥首席研究人员实现其成为一名成功的研究科学家的目标的潜力。相关性：在人类历史上，地球上第一次出现了吃得过饱的人超过了吃不饱的人。申请者的研究目标是了解脂肪组织的新陈代谢，以便找到一种方法将储存脂肪的细胞转化为燃烧脂肪的细胞。

DESCRIPTION (provided by applicant): This proposal details a 3-year training program to develop the skills necessary for candidate Eric Goetzman to become an independent research scientist. In July 2006 Dr. Goetzman assumed an assistant professor position at the University of Pittsburgh with 90% protected time for developing his research career. His scientific background is in the study of the acyl-CoA dehydrogenases (ACADs), a key family of mitochondrial fatty acid oxidation enzymes. Dr. Goetzman now wishes to transfer his knowledge of fatty acid oxidation into the study of obesity and adipose tissue biology. Dr. Jerry Vockley, a biochemical geneticist and expert on inborn errors of fatty acid oxidation, will mentor Dr. Goetzman's career training. Dr. Robert O'Doherty will act as co-sponsor. Dr. O'Doherty is an obesity/diabetes researcher and an expert in insulin and leptin signaling. His mentorship will provide the applicant with training in new methodologies and guidance in navigating the field of obesity research using animal models. Dr. Goetzman presents three key pieces of preliminary data: 1) knockout mice with reduced fatty acid oxidation have dysregulated fatty acid release from adipose tissue; 2) the insulin sensitizing drug rosiglitazone increases the expression and activity of fatty acid oxidation enzymes specifically in adipose tissue; and 3) fatty acid oxidation enzymes are subject to reversible acetylation which may regulate activity in adipose tissue. Three specific aims are proposed to investigate questions raised by the preliminary data. Aim 1 will use knockout mice and in vitro techniques to establish the importance of fatty acid oxidation as an energy source in adipose tissue. Aim 2 will test the hypothesis that rosiglitazone activates a signaling cascade resulting in the phosphorylation-induced activation of the transcription factor PPARalpha, which in turn increases the expression of fatty acid oxidation enzymes. Aim 3 will study the effect of enzyme acetylation on the rate of mitochondrial fatty acid oxidation in adipose tissue. Further, pure recombinant enzyme will be used to study the mechanism by which acetylation regulates activity. Understanding the regulation of fatty acid oxidation enzymes in adipose tissues is important for developing new anti-obesity therapies that shift adipocytes away from fat storage toward a more catabolic phenotype. The University of Pittsburgh is an ideal setting due to the strong research environment and the availability of outstanding mentors and consultants. This combination will maximize the potential for the principal investigator to realize his goal of becoming a successful research scientist. Relevance: For the first time in human history there are more overfed than underfed people on the planet. The applicant's research goal is to understand the metabolism of fat tissue in order find a way to convert fat-storing cells into fat-burning cells.