Targeting Neutrophils and Leukotrienes to Treat Type 2 Diabetes

针对中性粒细胞和白三烯治疗 2 型糖尿病

• 批准号: 8698022
• 负责人: STEVEN E SHOELSON
• 金额: $ 35.22万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8698022
• 关键词: Ablation; Address; Adipocytes; Adipose tissue; Adverse effects; Affect; Affinity; Albumins; Anabolism; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Arachidonate 5-Lipoxygenase; Arthritis; Asthma; Basic Science; Beta Cell; Blood Circulation; Blood Glucose; Cells; Chemotactic Factors; Chronic; Clinical; Clinical Research; Clinical Trials; Cre-LoxP; Data; Deposition; Diabetes Mellitus; Enzymes; Failure; Fatty Liver; Fatty acid glycerol esters; Flow Cytometry; Genetic; Glucose; Glucose Intolerance; Glycosylated hemoglobin A; Health; Hepatocyte; Host Defense; Immune response; Immunofluorescence Immunologic; Immunohistochemistry; Immunologics; Immunology; Inflammation; Injury; Insulin; Insulin Resistance; Interleukin-1; Intervention; Knock-out; LTB4R gene; Leukotriene B4; Leukotriene B4 Receptors; Leukotrienes; Link; Lipids; Lipoxygenase Inhibitors; Liver; Lung; Malignant Neoplasms; Metabolic; Metabolism; Methods; Monoclonal Antibodies; Mus; Myelogenous; Myeloid Cells; Neutrophil Infiltration; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathogenesis; Pathology; Patients; Phase; Phenotype; Process; Prodrugs; Production; Research; Research Design; Rodent; Role; Series; Signal Pathway; Site; Solid; Source; Testing; Tissue-Specific Gene Expression; Tissues; Translating; Translations; Ubenimex; Zileuton; adiponectin; cell type; eosinophil; fasting glucose; glucose tolerance; improved; inflammatory marker; inhibitor/antagonist; insulin tolerance; interest; leukotriene A4 hydrolase; macrophage; mast cell; mouse model; neutrophil; novel strategies; novel therapeutics; pilot trial; prevent; receptor; salicylate; salicylsalicylic acid

DESCRIPTION (provided by applicant): Obesity is accompanied by local and systemic changes related to chronic inflammation, which may promote insulin resistance, β cell failure and type 2 diabetes (T2D). Many experimental approaches and types of studies implicate inflammation in these conditions, but the ones likely to be most useful and important for patients with T2D have either high translational potential or clear avenues to clinical studies. We previously showed that NF-κB is activated in obesity and appears to promote pathologies associated with diabetes. We further showed that salicylates target NF-κB and lower glucose in obese rodents. We translated this anti-inflammatory approach to patients with T2D, first with small pilot trials and then larger TINSAL-T2D Phase 2 and 3 clinical trials. This application provides a new and exciting alternative approach to targeting inflammation in T2D that is entirely distinct from any previous attempt. In mice we found that neutrophils are rapidly upregulated in adipose tissue (AT) during the induction of obesity, and that six distinct methods for reducing neutrophil number and/or recruitment may provide consistent improvements in insulin resistance and glucose intolerance. The six distinct approaches include 1) Antibody depletion of neutrophils using a highly selective monoclonal antibody, 2) Genetic ablation of the enzyme leukotriene A4 hydrolase (Lta4h), which catalyzes production of the neutrophil chemoattractant, LTB4, 3) Genetic ablation of the high affinity LTB4 receptor, BLT1, and treatment of mice either with 4) Zileuton, a 5-lipoxygenase (5-LO) inhibitor approved for treating patients with asthma, 5) Bestatin, an LTA4H inhibitor, and 6) CP105696, a BLT1 receptor antagonist developed to treat arthritis and asthma. Preliminary results further show that these six distinct approaches all improve insulin resistance and glucose intolerance in parallel with diminishing neutrophil number and/or neutrophil recruitment to AT. However the six approaches do not selectively target AT, but their effects are systemic, potentially affecting all tissues and cell types. We therefore delineate which tissues are affected by the six interventions and which is responsible for the metabolic improvements. We initially focus on liver and lung, as these are established sites of neutrophil recruitment and involvement in host defense and tissue injury. However these tissues are also different, as liver steatosis accompanies obesity and contributes to T2D. By contrast, lung is neither thought to contribute to T2D nor accumulate lipid. We also develop a series of new mouse models to selectively block production of the neutrophil chemoattractant LTB4 in AT, liver and myeloid lineages. These approaches simultaneously identify sites for neutrophil recruitment leading to metabolic dysregulation and methods for reversal to provide metabolic improvements. Proposed studies provide a clear rationale and direct avenue for translating this new approach to patients with T2D.

描述（申请人提供）：肥胖伴随着与慢性炎症相关的局部和全身变化，这可能促进胰岛素抵抗、β细胞衰竭和2型糖尿病（T2D）。许多实验方法和研究类型都表明这些病症与炎症有关，但对 T2D 患者最有用和最重要的方法和研究类型要么具有较高的转化潜力，要么具有明确的临床研究途径。我们之前表明 NF-κB 在肥胖中被激活，并且似乎会促进与糖尿病相关的病理。我们进一步表明，水杨酸盐靶向 NF-κB 并降低肥胖啮齿动物的血糖。我们将这种抗炎方法应用于 T2D 患者，首先进行小型试点试验，然后进行更大规模的 TINS​​AL-T2D 2 期和 3 期临床试验。该应用提供了一种新的、令人兴奋的替代方法来靶向 T2D 炎症，这与之前的任何尝试完全不同。在小鼠中，我们发现在诱导肥胖期间，脂肪组织（AT）中的中性粒细胞迅速上调，并且减少中性粒细胞数量和/或募集的六种不同方法可以持续改善胰岛素抵抗和葡萄糖耐受不良。六种不同的方法包括 1) 使用高选择性单克隆抗体消除中性粒细胞，2) 对白三烯 A4 水解酶 (Lta4h) 进行基因消除，该酶催化中性粒细胞趋化剂 LTB4 的产生，3) 对高亲和力 LTB4 受体 BLT1 进行基因消除，以及对小鼠进行治疗 4) Zileuton，一种被批准用于治疗哮喘患者的 5-脂氧合酶 (5-LO) 抑制剂，5) Bestatin，一种 LTA4H 抑制剂，以及 6) CP105696，一种 BLT1 受体拮抗剂，开发用于治疗关节炎和哮喘。初步结果进一步表明，这六种不同的方法均可改善胰岛素抵抗和葡萄糖耐受不良，同时减少中性粒细胞数量和/或中性粒细胞向 AT 的募集。然而，这六种方法并不选择性地针对 AT，但它们的影响是系统性的，可能影响所有组织和 细胞类型。因此，我们描述了哪些组织受到六种干预措施的影响以及哪些组织负责代谢的改善。我们最初关注肝脏和肺，因为这些是中性粒细胞募集和参与宿主防御和组织损伤的既定部位。然而，这些组织也有所不同，因为肝脏脂肪变性伴随着肥胖并导致 T2D。相比之下，肺部既不被认为会导致 T2D，也不被认为会积聚脂质。我们还开发了一系列新的小鼠模型，以选择性地阻断 AT、肝脏和骨髓谱系中中性粒细胞趋化剂 LTB4 的产生。这些方法同时确定了导致代谢失调的中性粒细胞募集位点以及逆转以提供代谢改善的方法。拟议的研究为将这种新方法应用于 T2D 患者提供了明确的理由和直接途径。