权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
10444975
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/10444975
关键词：
Adolescent Adult Affect Americas 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-1 Interleukin-12 Interleukin-2 Interleukin-4 Islets of Langerhans Kidney Diseases Liver Fibrosis Microvascular Dysfunction Multiple Abnormalities Myocardial Infarction Non obese Non-Insulin-Dependent Diabetes Mellitus Organ Pathology Peripheral arterial disease Play Positioning Attribute Reporting Retinal Diseases Role Signal Transduction Stroke Structure Testing Time Tissues Type 2 diabetic adipokines base 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.