BMP-7 Modulates Inflammation induced cell death in Diabetic Cardiac and Skeletal Muscle

BMP-7 调节糖尿病心肌和骨骼肌炎症诱导的细胞死亡

基本信息

批准号：
9788441
负责人：
Rakesh C Kukreja
金额：
$ 58.7万
依托单位：
UNIVERSITY OF CENTRAL FLORIDA
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：
2018-09-19 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9788441
关键词：
Anti-inflammatory Apoptosis Attenuated CASP1 gene Caspase Cell Death Chronic Clinical Complications of Diabetes Mellitus Critical Care Cytokine Activation Data Development Diabetes Mellitus Diabetic mouse Disease Echocardiography Effectiveness Europe Fibrosis Functional disorder Goals Hand Strength Heart Hyperglycemia Immunohistochemistry Infiltration Inflammasome Inflammation Inflammatory Insulin-Dependent Diabetes Mellitus Interleukin-1 beta Interleukin-10 Interleukin-18 Interleukin-6 Knockout Mice Mediating Modeling Molecular Biology Techniques Mus Muscle Muscle function Myocardial dysfunction Myocardium Necrosis Non-Insulin-Dependent Diabetes Mellitus Organ Oryctolagus cuniculus Osteoporosis Oxidative Stress Pathogenesis Pathway interactions Patient-Focused Outcomes Patients Play Prediabetes syndrome Prevalence Recombinants Role Signal Transduction Skeletal Muscle Soleus Muscle Source TLR4 gene TNF gene Testing Therapeutic Type 2 diabetic attenuation base bone morphogenic protein clinical care cytokine diabetic diabetic patient heart function improved in vivo macrophage monocyte novel therapeutics receptor receptor function type I and type II diabetes type I diabetic

项目摘要

Project Summary The development and progression of diabetes involves oxidative stress and inflammation that leads to disorders in multiple organs including the cardiac and skeletal muscle. However, it remains unknown whether inflammation induced cell death, known as pyroptosis occurs in cardiac and skeletal muscle of diabetics. Our preliminary data shows that diabetic mice have enhanced infiltration of monocytes, pro-inflammatory toll-like receptor 4, NLRP3 inflammasome, activated caspase-1 and increased pro-inflammatory cytokines in the heart as well as skeletal muscle. Treatment with the recombinant bone morphogenic protein-7 (BMP-7) decreased hyperglycemia, inflammation and improved cardiac and muscle function. Based on these preliminary data, we hypothesize that BMP-7 increases anti-inflammatory M2 macrophages decreases pyroptosis, thereby improving cardiac and skeletal muscle function in diabetes. We propose to test this hypothesis through the following aims. 1: Diabetes causes cardiac and skeletal muscle dysfunction through increase of inflammatory cytokines, activation of NLRP3 inflammasome and caspase 1 regulated pyroptosis. 2: Treatment with BMP-7 differentiates monocytes into anti-inflammatory M2 macrophages resulting in amelioration of pyroptosis and adverse cardiac and skeletal muscle remodeling in diabetic mice. 3: Chronic treatment with BMP-7 ameliorates diabetic complications through suppression of inflammatory pathways and pyroptosis in a translational rabbit model of diabetes. The proposed studies will be carried out in the well-established models of Type 1 and Type 2 diabetes. We expect to elucidate the critical role of pyroptosis in causing cardiac and skeletal muscle dysfunction and the beneficial role of BMP-7 therapy in diabetes. These studies have the promise for critical care of diabetic patients, because BMP-7 is clinically approved for the treatment of osteoporosis patients in Europe.

项目摘要糖尿病的发育和进展涉及氧化应激和炎症导致多个器官的疾病，包括心脏和骨骼肌。但是，它炎症是否诱导细胞死亡（称为凋亡）仍然未知。糖尿病患者的心脏和骨骼肌。我们的初步数据表明糖尿病小鼠有增强单核细胞的浸润，促炎性Toll样受体4，NLRP3炎症体，激活的caspase-1并增加心脏中的促炎细胞因子以及骨骼肌肉。重组骨形态学蛋白-7（BMP-7）的处理降低高血糖，炎症以及改善的心脏和肌肉功能。基于这些初步数据，我们假设BMP-7增加了抗炎M2巨噬细胞减少凋亡，从而改善糖尿病的心脏和骨骼肌功能。我们建议通过以下目标检验这一假设。 1：糖尿病通过增加炎症引起心脏和骨骼肌功能障碍细胞因子，NLRP3炎性体和胱天蛋白酶1的激活调节凋亡。 2：用BMP-7处理将单核细胞区分为抗炎M2巨噬细胞导致改善凋亡以及不良心脏和骨骼肌肉重塑糖尿病小鼠。 3：BMP-7长期治疗通过抑制来改善糖尿病并发症糖尿病转化兔模型中的炎症途径和凋亡。拟议的研究将在良好的1型和2型模型中进行糖尿病。我们期望阐明凋亡在引起心脏和骨骼的关键作用 BMP-7治疗在糖尿病中的肌肉功能障碍和有益作用。这些研究有糖尿病患者重症监护的承诺，因为BMP-7经过临床批准欧洲骨质疏松症患者的治疗。