Validation of small molecule 12-lipoxygenase inhibitors in metabolic disease

小分子 12-脂氧合酶抑制剂在代谢疾病中的验证

• 批准号: 10130042
• 负责人: Raghavendra G Mirmira
• 金额: $ 5.41万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10130042
• 关键词: Validation; small; molecule; 12; lipoxygenase

 DESCRIPTION (provided by applicant): The crude prevalence of pre-diabetes and diabetes in the US is a staggering 40%. It is now widely recognized that deficiencies of ß cell mass and/or function are central in the transition from impaired glucose tolerance to frank diabetes in virtualy all forms of diabetes. In the setting of obesity and insulin resistance, the genesis of insulin secretory defects is multifactorial, and includes not only inflammatory pathways intrinsic to the cell, but also a network in which proinflammatory signals from the adipocyte and macrophage feed forward to impair ß cell function. This convergence on ß cell health suggests that common pathways of inflammation can be manipulated to protect ß cells in both type 2 diabetes (T2D) and type 1 diabetes (T1D). This grant application is a partnership between the laboratories of Drs. R. Mirmira and J. Nadler - with close collaborations with Dr. T. Holman and the NIH Chemical Genomics Center (NCGC) - and will focus on the early stage pharmacologic validation of novel human 12/15-lipoxygenase (12-LO) inhibitors for the prevention or reversal of metabolic disease. 12-LO catalyzes the oxygenation of cellular poly-unsaturated fatty acids to form lipid by-products such as 12-HPETE and 12-HETE, which impose inflammatory and oxidative stress within ß cells, causing their dysfunction and death. The strength of this application is the collaborative effort between MPIs and collaborators, who collectively will bring their expertise and unique reagents - including knockout mouse models, selective lead inhibitor compounds ML127 and ML355, and primary human cells - to bear on the preclinical validation of small molecule inhibitors of 12-LO in diabetes. We will test the hypothesis that inhibition of 12-LO with lead small molecule inhibitors will result in the prevention or mitigation of hyperglycemia in the setting of insulin resistance, T2D, and T1D. We propose the following 3 aims: Aim 1: Determine the efficacies and mechanism of lead 12-LO inhibitors in prevention and treatment of insulin resistance and T2D. Aim 2: Assess the efficacies of lead 12-LO inhibitors in prevention and treatment of ß cell dysfunction and death in T1D. Aim 3: Interrogate next generation 12-LO inhibitors potencies and molecular mechanisms in human islets. The strength of our approach lies in the unique reagents in our possession, notably, novel specific 12-LO inhibitors and conditional knockout mice. The primary impact of this proposal will be the identification and early-stage preclinical validation of 12-LO inhibitors for use in the prevention or treatment of T2D and T1D

 描述（由申请人提供）：在美国，糖尿病前期和糖尿病的粗患病率高达 40%，现在人们普遍认识到，β 细胞质量和/或功能的缺陷是从糖耐量受损向糖耐量受损转变的关键。在肥胖和胰岛素抵抗的情况下，胰岛素分泌缺陷的起源是多因素的，不仅包括细胞固有的炎症途径，还包括促炎症信号的网络。脂肪细胞和巨噬细胞前馈损害 ß 细胞功能，这表明可以操纵常见的炎症途径来保护 2 型糖尿病 (T2D) 和 1 型糖尿病 (T1D) 中的 ß 细胞。该应用程序是 R. Mirmira 博士和 J. Nadler 博士实验室之间的合作伙伴关系 - 与 T. Holman 博士和 NIH 化学基因组中心密切合作(NCGC) - 将重点关注新型人类 12/15-脂氧合酶 (12-LO) 抑制剂的早期药理学验证，以预防或逆转代谢疾病。12-LO 催化细胞多不饱和脂肪酸的氧化作用。形成脂质副产物，如 12-HPETE 和 12-HETE，在 ß 细胞内施加炎症和氧化应激，导致其功能障碍和死亡。该应用是 MPI 和合作者之间的共同努力，他们将共同利用他们的专业知识和独特的试剂——包括基因敲除小鼠模型、选择性先导抑制剂化合物 ML127 和 ML355 以及原代人类细胞——来进行小分子抑制剂的临床前验证。我们将检验用 12-LO 抑制的假设。 先导小分子抑制剂将在胰岛素抵抗、T2D 和 T1D 情况下预防或减轻高血糖。我们提出以下 3 个目标： 目标 1：确定先导 12-LO 抑制剂在预防和治疗中的功效和机制。目标 2：评估先导 12-LO 抑制剂在预防和治疗 β 细胞功能障碍和死亡方面的功效。 T1D. 目标 3：探究下一代 12-LO 抑制剂在人类胰岛中的效力和分子机制，我们的方法的优势在于我们拥有的独特试剂，特别是新型特异性 12-LO 抑制剂和条件性基因敲除小鼠。该提案的重点将是用于预防或治疗 T2D 和 T1D 的 12-LO 抑制剂的鉴定和早期临床前验证