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Interleukin 12 disruption provides beta cell and microvessel protection in type 2diabetes

白介素 12 破坏为 2 型糖尿病提供 β 细胞和微血管保护

基本信息

批准号：
10650143
负责人：
KHALID MATROUGUI
金额：
$ 44.92万
依托单位：
EASTERN VIRGINIA MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10650143
关键词：
Adolescent Adult Affect Antibodies Atherosclerosis Attenuated Autophagocytosis Beta Cell Blood Vessels Cardiomyopathies Cardiovascular system Cell physiology Cessation of life Data Diabetes Mellitus Diabetic mouse Disease Endothelial Cells Etiology Failure Fibrosis Functional disorder Genetic Health Hepatotoxicity Hyperglycemia Impaired wound healing Individual Inflammation Inflammatory Insulin Resistance Insulin-Dependent Diabetes Mellitus Interleukin-12 Islets of Langerhans Kidney Diseases Liver Fibrosis Microvascular Dysfunction Multiple Abnormalities Mus Myocardial Infarction Non obese Non-Insulin-Dependent Diabetes Mellitus Organ Pathology Peripheral arterial disease Positioning Attribute Reporting Retinal Diseases Role Signal Transduction Stroke Structure Testing Tissues Type 2 diabetic Vascular Endothelial Cell adipokines calcification clinically significant cytokine diabetic patient endoplasmic reticulum stress improved multidisciplinary novel renal damage

项目摘要

SUMMARY/ABSTRACT Beta cell failure, microvascular endothelial cell dysfunction, fibrosis, and calcification are clinically significant problems in type 2 diabetic (T2D) patients because they cause myocardial infarction, stroke, peripheral artery disease, retinopathy, nephropathy, cardiomyopathy, and wound healing delay. However, the detrimental mechanisms responsible for these pathologies in T2D are not completely understood. Current therapies for T2D neither halt nor reverse beta cell failure, endothelial cell dysfunction, nor the tissue complications. Therefore, there is a critical need for the identification of mechanism-based, treatable targets to improve beta cell and microvascular function, to reduce fibrosis and calcification, and to limit the abnormalities of multiple tissues and organs in T2D. Cytokine and adipokine secretion is increased in T2D, which affects beta cell and microvascular function and structure. Specifically, the level of the pro- inflammatory cytokine interleukin-12 (IL-12) is increased in adolescent and adult T2D patients. However, it is unknown whether the inhibition of IL-12 protects beta cell and microvascular function, thereby reducing fibrosis and calcification in multiple organs. Furthermore, the mechanism by which increased IL-12 might cause these pathologies is unknown. The premise is that IL-12 administration to non-obese mice leads to diabetes, liver toxicity and fibrosis, kidney damage, and atherosclerosis, supporting a detrimental role of IL- 12 in diabetes, and multiple tissues and organs damage. We hypothesize that increased IL-12 in T2D mice causes beta cell dysfunction, hyperglycemia, insulin resistance, microvascular endothelial cell dysfunction, fibrosis, and calcification through inflammation, endoplasmic reticulum (ER) stress, and autophagy mechanisms. To test the hypothesis, we proposed the following aims: Aim #1: IL-12 causes beta cell and endothelial cell dysfunction, fibrosis, and calcification in T2D. We will assess whether IL-12-induced pathology in T2D can be abrogated using genetic deletion of IL-12 or neutralizing IL- 12 antibody; Aim #2: IL-12 induces pancreatic islet inflammation in T2D. We will examine if genetic deletion of IL-12 or neutralizing IL-12 antibody in T2D mice attenuates the inflammation in pancreatic islets, and subsequently improves beta cell and endothelial cell function, and reduces fibrosis and calcification; Aim #3: IL-12 induced beta and endothelial cell dysfunction, fibrosis, and calcification are dictated by an ER stress mechanism in T2D. We will illustrate the mechanisms in beta cells and endothelial cells whereby IL-12 leads to beta cell and endothelial cell dysfunction, fibrosis and calcification in T2D; Aim #4: IL-12 induced beta cell and endothelial cell dysfunction, fibrosis, and calcification are driven by an autophagy mechanism in T2D. We will elucidate the mechanisms in beta cells and endothelial cells whereby IL-12 leads to beta cell and endothelial cell dysfunction, fibrosis, and calcification in T2D.

摘要/摘要 β细胞衰竭、微血管内皮细胞功能障碍、纤维化和钙化具有临床意义 2 型糖尿病 (T2D) 患者的问题，因为它们会导致心肌梗塞、中风、外周血动脉疾病、视网膜病、肾病、心肌病和伤口愈合延迟。然而，导致 T2D 病理的有害机制尚不完全清楚。当前的 T2D 疗法既不能阻止也不能逆转 β 细胞衰竭、内皮细胞功能障碍或组织损伤并发症。因此，迫切需要确定基于机制的可治疗目标改善β细胞和微血管功能，减少纤维化和钙化，并限制 T2D 中多个组织和器官的异常。 T2D 中细胞因子和脂肪因子的分泌增加，它影响β细胞和微血管的功能和结构。具体来说，亲的水平青少年和成人 T2D 患者的炎性细胞因子白细胞介素 12 (IL-12) 增加。然而，它尚不清楚 IL-12 的抑制是否可以保护 β 细胞和微血管功能，从而减少多个器官的纤维化和钙化。此外，增加 IL-12 的机制可能这些病症的原因尚不清楚。前提是对非肥胖小鼠施用 IL-12 会导致糖尿病、肝毒性和纤维化、肾损伤和动脉粥样硬化，支持 IL-的有害作用 12.糖尿病时，多组织器官损害。我们假设 T2D 中 IL-12 增加小鼠导致β细胞功能障碍、高血糖、胰岛素抵抗、微血管内皮细胞炎症、内质网 (ER) 应激导致的功能障碍、纤维化和钙化，和自噬机制。为了检验这一假设，我们提出了以下目标：目标 #1：IL-12 导致 T2D 中的 β 细胞和内皮细胞功能障碍、纤维化和钙化。我们将评估是否可以通过基因删除 IL-12 或中和 IL-12 来消除 T2D 中 IL-12 诱导的病理学 12抗体；目标#2：IL-12 在 T2D 中诱导胰岛炎症。我们将检查是否遗传 T2D 小鼠中 IL-12 的缺失或中和 IL-12 抗体可减轻胰岛的炎症，随后改善β细胞和内皮细胞功能，减少纤维化和钙化；目标 3：IL-12 诱导 β 细胞和内皮细胞功能障碍、纤维化和钙化 T2D 中的 ER 应激机制。我们将说明 β 细胞和内皮细胞的机制 IL-12 在 T2D 中导致 β 细胞和内皮细胞功能障碍、纤维化和钙化；目标#4： IL-12 诱导的 β 细胞和内皮细胞功能障碍、纤维化和钙化是由 T2D 中的自噬机制。我们将阐明β细胞和内皮细胞的机制 IL-12 会导致 2 型糖尿病 (T2D) 中的 β 细胞和内皮细胞功能障碍、纤维化和钙化。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Interleukin-1β Disruption Protects Male Mice From Heart Failure With Preserved Ejection Fraction Pathogenesis.

DOI：
10.1161/jaha.122.029668
发表时间：
2023-07-18
期刊：
JOURNAL OF THE AMERICAN HEART ASSOCIATION
影响因子：
5.4
作者：
Srinivas, Balaji K.;Bourdi, Aya;O'Regan, Jacob D.;Malavalli, Kumar D.;Rhaleb, Nour-Eddine;Belmadani, Souad;Matrougui, Khalid
通讯作者：
Matrougui, Khalid

Disrupting Interleukin 12 Improves Microvascular Endothelial Function in Type 2 Diabetes Through ER Stress CHOP and Oxidative Stress Mechanisms.