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Cytoprotection and the mechanism of action of a natural product Khellin against ER stress

天然产物 Khellin 对抗 ER 应激的细胞保护和作用机制

基本信息

批准号：
10285537
负责人：
Weidong Wang
金额：
$ 14.5万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10285537
关键词：
ATF6 gene Adipose tissue Animal Model Animals Atherosclerosis Award Beta Cell Blood Glucose Body Weight Cell Death Cell Survival Cell physiology Cells Cessation of life Chemicals Chronic Cytoprotection Defect Development Diabetes Mellitus Diabetic mouse Diet Disease Foundations Functional disorder Hyperglycemia Injections Insulin Insulin Resistance Liver Mus Natural Products Neurodegenerative Disorders Obese Mice Obesity Oral Parents Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Pilot Projects Play Proteins Public Health Research Role Skeletal Muscle Structure of beta Cell of islet Testing Time Work cell type clinical development diabetic dietary supplements endoplasmic reticulum stress high throughput screening human disease improved insulin sensitivity intraperitoneal mouse model novel response therapeutic target

项目摘要

Abstract Endoplasmic reticulum (ER) stress plays an important role in the pathogenesis of a growing list of human diseases, including diabetes, obesity, atherosclerosis, and neurodegenerative diseases. In diabetes, ER stress plays important roles in the pathogenesis of all types of diabetes; it is involved in β cell defects and in the development of insulin resistance in adipose tissue, liver, and skeletal muscles. Chronic ER stress leads to cell dysfunction and death through the hyperactivation of the unfolded protein response (UPR), and ER stress/UPR hyperactivation has therefore been proposed as a therapeutic target for the treatment of ER stress-associated diseases. However, no drugs on the market have been approved for targeting ER stress/UPR-induced cell dysfunction and death as their mode of action. In our parent R01 award, we have identified a natural product Khellin as a molecule of cytoprotection against ER stress in a high throughput screen. Khellin treatment via the intraperitoneal (i.p.) injection significantly ameliorates hyperglycemia and protects the function and survival of β cells in two diabetic mouse models caused by ER stress-induced β cell death. Furthermore, Khellin injection also significantly improved insulin sensitivity and reduced body weight in obese animal model. Importantly, we discovered that Khellin selectively inhibits the ER stress-induced activation of one of three UPR pathways, the IRE1a pathway, but with no effect on the other two UPR pathways: PERK and ATF6. These findings revealed for the first time that the natural product Khellin increases functional β cell mass, improves insulin resistance, and ameliorates diabetes and obesity by inhibiting ER stress-induced IRE1a hyperactivation. So far, in our parent R01 award, we have achieved these exciting results in animal models with Khellin treatment via the i.p. injection. In a pilot study, we have treated the Akita diabetic mice with Khellin added to diet and observed that similar to the i.p. injection, the oral treatment of Khellin also significantly lowered blood glucose levels in Akita mice. As a natural extension, in the Dietary Supplements application, we will test the hypothesis that oral Khellin improves diabetic and obese conditions by inhibiting IRE1a activation. We will test this hypothesis with two aims. In Aim 1, we will determine the effect of Khellin orally taken from diet on β cell function and survival in Akita diabetic mice. The effect of Khellin on ER stress/UPR in β cells will be examined. In Aim 2, we will determine the effect of orally taken Khellin in insulin sensitivity and obesity in diet-induced insulin resistant and obesity mouse model. The effect of Khellin on ER stress/UPR in adipose tissue, liver, and skeletal muscles will be examined. Together, this work will reveal that orally taken Khellin improves β cell function, insulin sensitivity, and overall diabetic and obese conditions in animals by inhibiting ER stress-induced IRE1a hyperactivation, thus establishing the foundation for the clinical development of Khellin as a novel dietary supplement for ER stress-related diseases.

抽象的内质网 (ER) 应激在越来越多的人类疾病的发病机制中发挥着重要作用疾病，包括糖尿病、肥胖、动脉粥样硬化和神经退行性疾病。在糖尿病中，ER 应激在所有类型糖尿病的发病机制中发挥重要作用；它与 β 细胞缺陷和脂肪组织、肝脏和骨骼肌中胰岛素抵抗的发展。慢性 ER 应激会导致细胞未折叠蛋白反应 (UPR) 和 ER 应激/UPR 过度激活导致功能障碍和死亡因此，过度激活被提议作为治疗 ER 应激相关的治疗靶点。疾病。然而，市场上还没有药物被批准用于靶向 ER 应激/UPR 诱导的细胞功能障碍和死亡作为其作用方式。在我们的母公司 R01 奖项中，我们确定了一种天然产品 Khellin 在高通量筛选中作为一种细胞保护分子，对抗 ER 应激。凯林治疗通过腹膜内 (i.p.) 注射可显着改善高血糖并保护 β 的功能和存活两种糖尿病小鼠模型中的细胞由内质网应激诱导的 β 细胞死亡引起。此外，凯林注射还显着提高了肥胖动物模型的胰岛素敏感性并减轻了体重。重要的是，我们发现 Khellin 选择性抑制 ER 应激诱导的三种 UPR 途径之一的激活，即 IRE1a 途径，但对其他两条 UPR 途径：PERK 和 ATF6 没有影响。这些发现揭示了首次发现天然产物 Khellin 增加功能性 β 细胞质量，改善胰岛素抵抗，并通过抑制 ER 应激诱导的 IRE1a 过度激活来改善糖尿病和肥胖症。到目前为止，在我们的母公司 R01 奖，我们通过 IP 进行 Khellin 治疗的动物模型取得了这些令人兴奋的结果。注射。在一项试点研究中，我们在饮食中添加了 Khellin 来治疗秋田糖尿病小鼠，并观察到：类似于 ip。注射、口服凯林也能显着降低秋田犬的血糖水平老鼠。作为自然延伸，在膳食补充剂应用中，我们将测试以下假设：口服 Khellin 通过抑制 IRE1a 激活来改善糖尿病和肥胖状况。我们将测试这个假设两个目标。在目标 1 中，我们将确定从饮食中口服 Khelin 对 β 细胞功能和存活的影响在秋田糖尿病小鼠中。将检查 Khellin 对 β 细胞 ER 应激/UPR 的影响。在目标 2 中，我们将确定口服 Khelin 对胰岛素敏感性和饮食引起的胰岛素抵抗和肥胖的影响肥胖小鼠模型。 Khellin 对脂肪组织、肝脏和骨骼肌 ER 应激/UPR 的影响将被检查。总之，这项工作将揭示口服 Khelin 可以改善 β 细胞功能、胰岛素通过抑制 ER 应激诱导的 IRE1a 来提高动物的敏感性以及整体糖尿病和肥胖状况过度激活，从而为 Khellin 作为新型膳食的临床开发奠定了基础补充 ER 应激相关疾病。