Investigation of FFAR2 as a novel regulator of pancreatic beta cell function

FFAR2 作为胰腺 β 细胞功能新型调节剂的研究

基本信息

批准号：
8837825
负责人：
Stephanie Renee Niemczyk
金额：
$ 3.87万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8837825
关键词：
Acetates Agonist Apoptosis Beta Cell Biological Assay Cell Line Cell Proliferation Cell physiology Cells Coupling Data Development Diabetes Mellitus Diet Dissection Drug Design Drug Targeting Evaluation Exhibits Failure Fatty acid glycerol esters Female Financial compensation G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs GTP-Binding Proteins Genes Genetic Glucose Hyperglycemia Hyperplasia Hypertrophy Insulin Insulin Resistance Investigation Islets of Langerhans Lead Ligands Mediating Mediator of activation protein Metabolism Modeling Mus Non-Insulin-Dependent Diabetes Mellitus Nonesterified Fatty Acids Obesity Outcome Study Pancreas Pertussis Toxin Phospholipase C Pregnancy Property Regulation Role Signal Pathway Signal Transduction Structure of beta Cell of islet Testing Time Volatile Fatty Acids Work base blood glucose regulation citrate carrier effective therapy genetic approach impaired glucose tolerance insulin secretion insulin signaling islet male mouse free fatty acid 2 receptor mouse model new therapeutic target novel preference pregnant protein kinase D public health relevance receptor research study response sex

项目摘要

DESCRIPTION (provided by applicant): The identification of novel drug targets is critical to the development of effective therapies for type 2 diabetes (T2D). Recent work by our lab and others has found that pancreatic islet expression of the recently de-orphanized GPCR, Free Fatty Acid Receptor 2 (FFAR2), is up regulated in mouse models of insulin resistance, such as pregnancy, obesity, and diabetes. These findings suggest that the receptor may be involved in mechanisms of ? cell adaptation to insulin resistance, and therefore a novel therapeutic target for T2D. Thus far, using pregnancy as a model of insulin resistance, our lab has found genetic deletion of FFAR2 (FFAR2-/-) to result in impaired glucose tolerance from diminished insulin secretion in FFAR2-/- females. Further, we have found that FFAR2-/- females exhibit incomplete ? cell mass expansion during pregnancy as a result of impaired hyperplasia and hypertrophy of the pancreatic beta cells. Together, these data support a role for FFAR2 in the regulation of ? cell function. Therefore, we will directly investigate the role of FFAR2 in regulating glucose stimulated insulin secretion and pancreatic ? cell mass in male mice under normal conditions and diet-induced obesity. Additionally, the proposed studies will define the mechanism by which FFAR2 mediates pancreatic ? cell function. The results of these studies will help in the evaluation of this potential novel therapeutic target for T2D.

描述（由申请人提供）：新型药物靶标的鉴定对于开发2型糖尿病（T2D）的有效疗法至关重要。我们的实验室和其他人的最新工作发现，在胰岛素抵抗的小鼠模型（例如妊娠，肥胖和糖尿病）中，胰岛胰岛表达的胰岛表达（FFAR2）在最近去甲烷化的GPCR的胰岛表达受到调节。这些发现表明该受体可能参与了机制？细胞适应胰岛素抵抗，因此是T2D的新型治疗靶标。到目前为止，使用妊娠作为胰岛素抵抗模型，我们的实验室发现FFAR2（FFAR2 - / - ）的遗传缺失导致FFAR2 - / - 女性中胰岛素分泌减少的葡萄糖耐受性受损。此外，我们发现FFAR2 - / - 女性表现不完整？胰腺β细胞的增生和肥大受损，在怀孕期间的细胞质量扩大。这些数据共同支持FFAR2在调节中的作用？细胞功能。因此，我们将直接研究FFAR2在调节葡萄糖刺激的胰岛素分泌和胰腺中的作用？在正常情况下雄性小鼠的细胞肿块和饮食诱发的肥胖症。此外，拟议的研究将定义FFAR2介导胰腺的机制？细胞功能。这些研究的结果将有助于评估T2D的潜在新型治疗靶点。