Investigation of the Therapeutic Potential of Fibroblast Activation Protein Inhibition in Type 2 Diabetes

成纤维细胞激活蛋白抑制治疗 2 型糖尿病的治疗潜力研究

• 批准号: 9357372
• 负责人: BRANDON LEE PANARO
• 金额: $ 5.03万
• 依托单位: SINAI HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-22 至 2019-09-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9357372
• 关键词: Accounting; Address; Adherence; Affinity; Antidiabetic Drugs; Biological Assay; Biology; Blood Circulation; Blood Glucose; Body Weight; Cause of Death; Clinical; Collaborations; Development; Diabetes Mellitus; Diet; Dipeptidyl Peptidases; Disease; Disease Management; Drug Targeting; Endopeptidases; Enzyme Inhibition; Enzymes; Epidemic; Epithelial; Exhibits; FAP gene; Functional disorder; Future; Genetic; Glucose; Goals; Health Care Costs; Hormones; Hypoglycemia; Investigation; Kidney Diseases; Knock-out; Knockout Mice; Legal patent; Link; Measurement; Mediating; Metabolic; Metabolic Diseases; Mission; Mus; Mutant Strains Mice; National Institute of Diabetes and Digestive and Kidney Diseases; Neuropathy; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathway interactions; Patients; Peptide Hydrolases; Pharmacology; Pharmacotherapy; Phenotype; Physiological; Population; Prevention; Preventive measure; Protein Deficiency; Protein Inhibition; Proteins; Publishing; Quality of life; Regulation; Reporting; Research; Resistance; Retinal Diseases; Risk; Role; Route; Substrate Specificity; Therapeutic; Tissues; Treatment Efficacy; United States; Universities; Up-Regulation; Wild Type Mouse; World Health Organization; anticancer research; base; blood glucose regulation; cost; diabetic; diabetic patient; effective therapy; experimental study; fibroblast-activating factor; genetic manipulation; glucagon-like peptide 1; glycylproline; good diet; healthy lifestyle; improved; inhibitor/antagonist; insulin secretion; interest; metabolic phenotype; mimetics; mouse model; mutant; novel; novel drug class; novel therapeutic intervention; peptide hormone; research clinical testing; small molecule inhibitor; statistics; targeted cancer therapy; treatment strategy; tumor

Project Summary Globally, the number of people with type 2 diabetes mellitus (T2D) is approaching 350 million [1]. With this number rapidly rising, the urgent need for effective therapeutics to treat this disease is also increasing. Research efforts have produced significant advances in treatment options, including the introduction of dipeptidyl peptidase 4 (DPP4) inhibitors, glucagon-like peptide-1 (GLP-1) mimetics and SGLT2 inhibitors to improve glucose-stimulated insulin secretion and lower blood glucose. Despite these advances, there remains a gap in the normalization of glucose and the prevention of complications among the population that current treatments have been unable to address, leaving millions of patients with insufficient and unsafe levels of glucose control. Recently, a protease enzyme called fibroblast activation protein (FAP) has emerged as a potential target for the treatment of T2D and obesity [2]. FAP is the most closely related enzyme to DPP4 [3, 4], a validated drug target. Multiple pharmacological inhibitors of DPP4 are now widely used in patients with T2D [5]. Previous interest in FAP has focused on its potential as a target for cancer therapy due to its upregulation in epithelial tumors [6]. However, recent FAP-specific activity assays have identified FAP activity in the circulation, as well as in several tissues with roles in metabolic regulation [7]. Most intriguingly, preliminary characterization of a global FAP knockout (Fap-/-) mouse demonstrated a) significant protection against diet-induced obesity and b) improved glycemia, phenotypic findings similar to those described in the global DPP4 knockout (Dpp4-/-) mouse [2]. Importantly, FAP has a unique endopeptidase activity, suggesting that its enzymatic targets are different from those of DPP4. Thus, FAP inhibition may provide a novel route to treatment of diabetes. We have independently generated mutant Fap-/- mice, enabling us to determine the metabolic phenotype ensuing from genetic FAP deficiency. Complementary experiments will utilize a potent and specific FAP inhibitor, compound 5057, to determine whether pharmacological FAP inhibition produces the same metabolic benefits observed in Fap-/- mice. Fap-/- mice and wild-type mice treated with compound 5057 will be employed to identify physiological mechanisms (and FAP substrates) underlying the metabolic benefits of FAP inactivation. We are hopeful that this research will lay the groundwork for clinical testing of a new class of drugs for the treatment of T2D.

项目摘要 在全球范围内，2型糖尿病(T2D)的人数正接近3.5亿[1]。 随着这一数字的迅速上升，迫切需要有效的治疗方法来治疗这种疾病 越来越多。研究工作在治疗方案方面取得了重大进展，包括 二肽基肽酶4(DPP4)抑制剂、胰高血糖素样肽-1(GLP-1)模拟物和 SGLT2抑制剂可改善葡萄糖刺激的胰岛素分泌和降低血糖。尽管 这些进展，在血糖正常化和预防糖尿病方面仍然存在差距。 目前的治疗方法无法解决的人群并发症，留下了 数以百万计的患者血糖控制水平不足和不安全。 最近，一种名为成纤维细胞激活蛋白(FAP)的蛋白酶已经成为一种潜在的 T2D和肥胖症的治疗目标[2]。FAP是与DPP4关系最密切的酶[3， 4]，一个有效的药物靶点。DPP4的多种药物抑制剂现在被广泛用于 T2D患者[5]。之前对FAP的兴趣主要集中在它作为癌症靶点的潜力上 由于其在上皮性肿瘤中上调的治疗作用[6]。然而，最近的FAP特异性活性分析表明 已经确定了FAP在循环中的活性，以及在几个与代谢有关的组织中的活性 条例[7]。最有趣的是，全球FAP基因敲除(Fap-/-)小鼠的初步特征 证明了a)对饮食诱导的肥胖有显著的保护作用，b)改善了血糖 表型发现类似于在全球DPP4基因敲除(DPP4-/-)小鼠中描述的那些[2]。 重要的是，FAP具有独特的内肽酶活性，这表明它的酶靶标是 与DPP4不同。因此，抑制FAP可能为糖尿病的治疗提供一条新的途径。 我们已经独立产生了突变的Fap-/-小鼠，使我们能够确定代谢 表型由遗传性FAP缺陷引起。互补性实验将利用一种强有力的 特定的FAP抑制剂，化合物5057，以确定药物对FAP的抑制 产生与在Fap-/-小鼠中观察到的相同的代谢益处。FAP-/-小鼠和野生型小鼠 将使用化合物5057来鉴定生理机制(和FAP底物) 潜在的FAP失活的代谢益处。我们希望这项研究将为 为治疗T2D的新药的临床测试奠定基础。