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，周围动脉疾病，视网膜病，肾病，心肌病和伤口愈合延迟。但是，对T2D中这些病理的有害机制尚未完全理解。当前的 T2D的疗法既不停止或反向β细胞衰竭，内皮细胞功能障碍，也没有组织并发症。因此，迫切需要识别基于机制的可处理目标改善β细胞和微血管功能，以减少纤维化和钙化，并限制 T2D中多个组织和器官的异常。 T2D中的细胞因子和脂肪因子分泌增加，影响β细胞以及微血管功能和结构。具体而言，pro的水平青少年和成年T2D患者的炎症性细胞因子白细胞素12（IL-12）增加。但是，它尚不清楚IL-12的抑制是否保护β细胞和微血管功能，从而降低多个器官中的纤维化和钙化。此外，增加IL-12的机制可能因为这些病理是未知的。前提是非肥胖小鼠的IL-12给药导致糖尿病，肝毒性和纤维化，肾脏损伤和动脉粥样硬化，支持IL-的有害作用糖尿病中有12个，多个组织和器官损害。我们假设T2D中的IL-12增加了小鼠引起β细胞功能障碍，高血糖，胰岛素抵抗，微血管内皮细胞通过炎症，内质网（ER）应力，功能障碍，纤维化和钙化，和自噬机制。为了检验假设，我们提出了以下目的：目标＃1：IL-12 引起β细胞和内皮细胞功能障碍，纤维化和T2D的钙化。我们将评估是否可以使用IL-12的遗传缺失来消除IL-12诱导的T2D中的病理或中和IL- 12抗体； AIM＃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或中和IL-12抗体的缺失减弱了胰岛的炎症，随后改善β细胞和内皮细胞功能，并减少纤维化和钙化； AIM＃3：IL-12诱导的β和内皮细胞功能障碍，纤维化和钙化被指示通过T2D中的ER应力机制。我们将说明β细胞和内皮细胞中的机制 IL-12导致β细胞和内皮细胞功能障碍，T2D中的纤维化和钙化； AIM＃4： IL-12诱导的β细胞和内皮细胞功能障碍，纤维化和钙化由 T2D中的自噬机制。我们将阐明β细胞和内皮细胞中的机制因此，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。

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.