Probing the adipocyte-myocyte axis: An Interdisciplinary Approach

描述(申请人提供)：新出现的肥胖大流行正在推动胰岛素抵抗形式的糖尿病患病率令人震惊地增加。肥胖导致胰岛素抵抗的机制仍未完全阐明。慢性卡路里过量会导致脂肪衍生脂肪酸(FA)和细胞因子向骨骼肌和心脏等胰岛素反应组织的输送增加，这可能导致毒性效应(细胞“脂毒性”)。心肌细胞脂肪毒性与线粒体紊乱、胰岛素抵抗、糖耐量异常和横纹肌功能障碍有关，但因果关系尚未建立。此外，在细胞脂毒反应中起保护作用或致病作用的分子调控通路尚未确定。我们认为，解决这一问题的传统单一学科方法不能有效地解决这一复杂的过程。因此，我们计划在伯纳姆医学研究所(BIMR)建立一个跨学科的研究团队来解决这一重要问题。这项为期一年的R24种子计划提案的具体目标是：1)召集一支跨科学学科的研究团队，包括生物学、分子医学、药物化学、药理学、纳米科学工程、生物信息学和生理学，以开发和测试策略，描述参与细胞信号事件网络的途径和分子，以及 驱动脂肪细胞-心肌细胞代谢重编程的下游基因调控反应 卡路里过剩状态；2)建立体内和基于细胞的系统，以支持 结合肌肉和蛋白质的互补遗传和小分子高通量筛查 脂肪表型终点和；3)生成初步数据以建立概念验证 并申请支持建立一个由R24资助的正式研究团队。《长河》 这个项目的学期目标是揭示新的致病机制范例，并确定新的 有望成为治疗靶点和与之相关的生物标志物的分子和途径 2型糖尿病及其并发症的治疗。 与公共健康相关：我们目前目睹了肥胖在美国的流行，这推动了糖尿病患病率史无前例的上升。我们召集了一个来自不同学科的科学家团队，共同解决这一重要问题。我们将在一个科学团队中利用生物学、遗传学、化学、生理学和工程学的优势，为预防和治疗糖尿病及其并发症寻找新的诊断标记和治疗方法。

DESCRIPTION (provided by applicant): The emerging obesity pandemic is driving an alarming increase in the prevalence of insulin resistant forms of diabetes. The mechanisms whereby obesity leads to insulin resistance remain to be fully elucidated. Chronic caloric excess leads to increased delivery of adipose-derived fatty acids (FA) and cytokines to insulin responsive tissues such as skeletal muscle and heart, which can result in toxic effects (cellular "lipotoxicity"). Myocyte lipotoxicity is associated with mitochondrial derangements, insulin resistance, glucose intolerance, and striated muscle dysfunction, yet cause-effect relationships have not been established. Moreover, the molecular regulatory pathways that are protective or pathogenic in the cellular lipotoxic response have not been defined. We propose that traditional single disciplinary approaches to this problem cannot effectively address this complex process. Therefore, we plan to establish an interdisciplinary research team at the Burnham Institute for Medical Research (BIMR) to address this important problem. The specific objectives of this one year R24 Seed planning proposal are: 1) to assemble a team of investigators across scientific disciplines including biology, molecular medicine, medicinal chemistry, pharmacology, nanoscience engineering, bioinformatics, and physiology to develop and test strategies that will delineate pathways and molecules involved in the network of cellular signaling events and downstream gene regulatory responses that drive adipocyte-myocyte metabolic reprogramming in states of caloric excess; 2) to establish in vivo and cell-based systems that will support complementary genetic and small molecule high-throughput screens using combined muscle and adipose phenotypic endpoints and; 3) to generate preliminary data to establish proof-of-concept and for the support of an application to establish a formal R24-supported research team. The long term goal of this project is to unveil new mechanistic pathogenic paradigms and to identify novel molecules and pathways that show promise as therapeutic targets and biomarkers relevant to treatment of type 2 diabetes and its complications. PUBLIC HEALTH RELEVANCE: We are currently witnessing an epidemic of obesity in the US, which is driving an unprecedented increase in the prevalence of diabetes. We have assembled a team of scientists from a variety of different disciplines to come together to address this important problem. We will use the strengths of biology, genetics, chemistry, physiology, and engineering in a single scientific team to identify new diagnostic markers and therapies for the prevention and treatment of diabetes and its complications.