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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.

摘要内质网应激（endoplasmic reticulum，ER）在越来越多的人类肿瘤的发病机制中起着重要作用疾病，包括糖尿病、肥胖症、动脉粥样硬化和神经退行性疾病。在糖尿病中，在所有类型糖尿病的发病机制中起重要作用;它参与β细胞缺陷和糖尿病的发病机制。脂肪组织、肝脏和骨骼肌中胰岛素抵抗的发展。慢性内质网应激导致细胞通过未折叠蛋白反应（UPR）和ER应激/UPR的过度激活而导致功能障碍和死亡因此，已经提出将超活化作为治疗ER应激相关性疾病的治疗靶标。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他们的行动模式。在我们的R 01奖项中，我们发现了一种天然产品， Khellin在高通量筛选中作为针对ER应激的细胞保护分子。Kellin治疗通过腹腔内注射注射液可明显改善高血糖，保护β-淀粉样蛋白的功能和存活。 ER应激诱导的β细胞死亡引起的两种糖尿病小鼠模型中的细胞。此外，克林注射液还显著改善胰岛素敏感性并降低肥胖动物模型的体重。重要的是我们发现Khellin选择性地抑制ER应激诱导的三种UPR途径之一的激活， IRE 1a通路，但对其他两条UPR通路：PERK和ATF 6没有影响。这些发现揭示了首次证明天然产物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IRE 1a过度活化来改善糖尿病和肥胖症。到目前为止，在我们的在获得R 01专利的同时，我们在动物模型中通过腹膜内注射Khellin治疗取得了这些令人兴奋的结果。注射在一项初步研究中，我们用添加到饮食中的Khellin治疗秋田糖尿病小鼠，并观察到，与腹膜内注射相似，口服Khellin也显著降低了秋田小鼠的血糖水平小鼠作为一个自然的延伸，在膳食补充剂的应用程序，我们将测试假设，口服 Khellin通过抑制IRE 1a活化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Khellin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细胞中ER应激/UPR的影响。在目标2中，我们将确定口服Khellin在饮食诱导的胰岛素抵抗中对胰岛素敏感性和肥胖的影响，肥胖小鼠模型。Khellin对脂肪组织、肝脏和骨骼肌中ER应激/UPR的影响将接受检查。总之，这项工作将揭示口服Khellin改善β细胞功能，胰岛素通过抑制ER应激诱导的IRE 1a，超活化，从而为Khellin作为一种新型膳食的临床开发奠定了基础补充ER压力相关疾病。