Nicotinamide N-methyltransferase (NNMT) in obesity and insulin resistance

描述（由申请人提供）：本提案描述了一个为期5年的项目，用于培训申请人，以实现其成为糖尿病研究独立研究者的目标。培训和职业发展计划包括具有潜在临床应用的引人注目的研究项目，实验室技术培训以及教学科学和职业发展研讨会和课程。Barbara Kahn博士是胰岛素抵抗和肥胖领域公认的领导者，将指导申请人的科学发展。她培养了许多博士后研究员，他们现在在学术机构担任教职。申请人选择Robert Gerszten博士作为共同导师。Gerszten博士是马萨诸塞州总医院的医学副教授。Gerszten博士和Kahn博士都是布罗德研究所的准会员。Gerszten博士一直是心血管和代谢疾病代谢组学分析的先驱。此外，由知名专家组成的咨询委员会将提供科学和职业建议。该项目的总体目标是确定烟酰胺N-甲基转移酶（NNMT）在调节体重和胰岛素敏感性中的作用。NNMT是将烟酰胺转化为N-甲基烟酰胺的酶。NNMT在脂肪细胞和肝脏中以高水平表达。然而，它在肥胖和糖尿病中的作用尚不清楚。申请人的初步数据显示，NNMT表达在肥胖小鼠模型的脂肪组织和肝脏中增加。用反义寡核苷酸（阿索）敲低高脂饮食小鼠脂肪组织和肝脏中的NNMT，诱导精胺/亚精胺乙酰转移酶（SSAT）的表达，这是调节脂肪组织中多胺通量的关键酶，并导致消瘦。肝细胞中NNMT的过表达导致葡萄糖产生增加。目的#1是确定改变的多胺通量是否介导由NNMT敲低引起的贫乏。目的#2是确定脂肪组织中NNMT的过表达是否导致肥胖，以及这是否是由多胺通量的抑制引起的。这将通过建立新的脂肪NNMT转基因小鼠来实现。目的#3是使用代谢组学分析鉴定可能导致肥胖和胰岛素抵抗的肥胖症中的新NNMT调节代谢物。目的#4是确定NNMT是否通过激活Sirt 1，PGC-1a和FOXO 1来增强肝脏再生。该项目将阐明一种新分子和新途径在肥胖和2型糖尿病中的作用。贝斯以色列女执事医疗中心的医学系和内分泌科为培训医生科学家提供了理想的环境。申请人还可以访问布罗德研究所的资源，包括代谢组学平台和生物信息学。这些优秀的资源将最大限度地提高申请人成功过渡到独立调查员的潜力。

DESCRIPTION (provided by applicant): This proposal describes a 5 year project for training the applicant to achieve his goal to become an independent investigator in diabetes research. The training and career development plan include a compelling research project with potential clinical applications, training in laboratory techniques, and didactic scientific and career development seminars and courses. Dr. Barbara Kahn, a well-recognized leader in the field of insulin resistance and obesity, will mentor the applicant's scientific development. She has trained numerous postdoctoral fellows who now have faculty positions in academic institutions. The applicant chooses Dr. Robert Gerszten as a co-mentor. Dr. Gerszten is an Associate Professor of Medicine at Massachusetts General Hospital. Both Drs. Gerszten and Kahn are Associate members of the Broad Institute. Dr. Gerszten has been a pioneer in metabolomic analysis of cardiovascular and metabolic diseases. In addition, an advisory committee of highly-recognized experts will provide scientific and career advice. The overall goal of the project is to determine the role of Nicotinamide N-methyltransferase (NNMT) in regulating body weight and insulin sensitivity. NNMT is an enzyme that converts nicotinamide to N-methylnicotinamide. NNMT is expressed at high levels in adipocytes and liver. However its role in obesity and diabetes is not clear. The applicant's preliminary data show that NNMT expression is increased in adipose tissue and liver of obese mouse models. Knockdown of NNMT with antisense oligonucleotides (ASO) in adipose tissue and liver of mice fed a high fat diet induces expression of spermine/spermidine acetyltransferase (SSAT), a key enzyme regulating polyamine flux in adipose tissue, and causes leanness. Overexpression of NNMT in hepatocytes results in increased glucose production. Aim #1 is to determine whether altered polyamine flux mediates the leanness caused by knockdown of NNMT. Aim #2 is to determine whether overexpression of NNMT in adipose tissue causes obesity and whether this results from inhibition of polyamine flux. This will be achieved by establishing new adipose NNMT transgenic mice. Aim #3 is to identify novel NNMT-regulated metabolites in adipoctyes that may contribute to obesity and insulin resistance using metabolomics analysis. Aim #4 is to determine whether NNMT enhances hepatic gluconeogenesis by activating Sirt1, PGC-1a and FOXO1. This project will elucidate the role of a novel molecule and novel pathways in obesity and type 2 diabetes. The Department of Medicine and Division of Endocrinology at Beth Israel Deaconess Medical Center provide an ideal setting for training physician-scientists. The applicant will also have access to the resources of the Broad Institute including the metabolomics platform and bioinformatics. These outstanding resources will maximize the potential for the applicant to successfully transition to an independent investigator.