Aging, Inflammation and Exercise in Chronic Stroke

慢性中风的衰老、炎症和运动

基本信息

批准号：
7372550
负责人：
CHARLENE E HAFER-MACKO
金额：
$ 49.75万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-05-15 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7372550
关键词：
5&apos -AMP-activated protein kinase Abdomen Activities of Daily Living Acute-Phase Proteins Adipocytes Adipose tissue Adult Affect Age Age-Years Aging Anti-Inflammatory Agents Anti-inflammatory Biological Biology Biopsy Blood Vessels Body Composition Cardiovascular Diseases Cardiovascular system Chronic Clinic Clinical Cytokine Receptors Data Diabetes Mellitus Disease Disuse Atrophy Education Educational Intervention Effectiveness Elderly Elevation Enzymes Euglycemic Clamping Event Exercise Fatty acid glycerol esters Glucose Clamp Glycogen (Starch) Synthase Health Heart Diseases High Prevalence Homeostasis Hyperinsulinism IRS1 gene Individual Inflammation Inflammatory Insulin Insulin Resistance Interleukins Intervention Intramuscular Knock-out Knowledge Lead Leg Life Style Limb structure Link Measurement Mediating Mediator of activation protein Medical Metabolic Metabolic syndrome Mitogen-Activated Protein Kinases Modeling Modification Molecular Muscle Muscle function Myomatous neoplasm Neurologic Non-Insulin-Dependent Diabetes Mellitus Numbers OGTT Obese Mice Outcome Patients Persons Phosphorylation Physiological Play Population Population Heterogeneity Process Proteins Race Randomized Recurrence Regulation Reporting Research Resistance development Risk Risk Factors Role Signal Transduction Skeletal Muscle Skeletal system Stretching Stroke Surrogate Markers Survivors TNFRSF1B gene Thigh structure Tissues Training Transcript Translational Research Tumor Necrosis Factor Receptor Tumor Necrosis Factor-alpha Tumor Necrosis Factors United States adipokines adiponectin aged basal insulin base cerebrovascular chronic stroke cytokine diabetes risk diabetic disorder risk fitness glucose tolerance glucose uptake hemiparesis hemiparetic stroke human MAPK14 protein human TNF protein impaired glucose tolerance improved insight insulin receptor substrate 1 protein insulin sensitivity insulin signaling motor neuron injury non-diabetic novel post stroke receptor receptor expression response sex stress-activated protein kinase 1 wasting

项目摘要

DESCRIPTION (provided by applicant): Systemic inflammation plays a critical role in atherosclerotic diseases and with cardiovascular and cerebrovascular events, insulin resistance, and the development of type 2 diabetes. Adipocytes of insulin resistant individuals produce and secrete larger amounts of these adipokines and bioactive molecules with the exception of adiponectin, an anti-inflammatory and insulin-sensitizing adipokine. Skeletal muscle adipokine receptors may dictate the impact of these circulating proteins on the degree of insulin resistance and systemic inflammation. Inflammation is a risk factor for stroke and contributes to the progression of cardiovascular disease. Moreover, there is a high prevalence of hyperinsulinemia and individuals are at increased risk for diabetes after stroke. The fundamental hypothesis of this study is that key inflammatory markers (TRNa, adiponectin) in adipose tissue and skeletal muscle are abnormal, skeletal muscle insulin signaling is impaired, and systemic insulin sensitivity is reduced in hemiparetic stroke patients and that these factors are modifiable and improved by exercise training in stroke patients. The aims of this study are the following: 1) To determine whether key systemic (TRNa and adiponectin circulating levels) and tissue (adipose tissue and skeletal muscle) inflammation (secretion, expression, and cytokine receptor TNFR1, TNFR2, adipoR1, adipoR2 expression) are disturbed in chronic stroke compared to age, sex, BMI, race, and risk-factor matched non-stroke controls and whether a 6-month randomized treadmill training intervention modifies these inflammatory markers in stroke patients; and 2) To determine whether a 6-month randomized treadmill training intervention improves systemic insulin sensitivity compared to stretch control in stroke patients by altering downstream signaling (AMPK, JNK, IRS1- Ser307, Akt and p-38 MAPK phosphorylation) and GS activity in hemiparetic and nonparetic leg skeletal muscles. To accomplish these aims, 90 subjects (n=18 controls and n=72 hemiparetic stroke patients) aged 55-75 years, BMI 20-35 kg/m2 will undergo abdominal and gluteal adipose tissue biopsies, and basal and insulin-stimulated vastus lateralis muscle biopsies during hyperinsulinemic-euglycemic clamps. Stroke subjects will be assigned to 6 month treadmill or education/stretch control intervention using a one-two-one randomization blocked on race, sex, and glucose tolerance status. This clinical translational research trial takes physiological outcomes from the clinic to the bench to determine the molecular mechanisms underlying the systemic insulin resistance in stroke compared to age and risk-factor matched non-stroke controls and whether treadmill training reduces inflammation and improves systemic insulin sensitivity in stroke. Direct measurement of inflammatory modulators in adipose tissue and skeletal muscle will provide novel information as to whether selected cytokines adversely affect insulin signaling at the skeletal muscle. Furthermore, the mechanistic findings will provide the first evidence of the molecular mechanisms by which treadmill training improves inflammatory regulators in adipose tissue and skeletal muscle and improves insulin signaling and action in skeletal muscle to increase insulin sensitivity in older stroke patients. This research will identify a strategy to treat insulin resistance in stroke survivors and establish the biological basis for recommending lifestyle modifications to reduce inflammation and improve the metabolic profile in stroke.

描述（由申请人提供）：全身炎症在动脉粥样硬化疾病、心脑血管事件、胰岛素抵抗和 2 型糖尿病的发展中起着至关重要的作用。胰岛素抵抗个体的脂肪细胞产生并分泌大量的这些脂肪因子和生物活性分子，但脂联素（一种抗炎和胰岛素敏化脂肪因子）除外。骨骼肌脂肪因子受体可能决定这些循环蛋白对胰岛素抵抗和全身炎症程度的影响。炎症是中风的危险因素，并导致心血管疾病的进展。此外，高胰岛素血症的患病率很高，个人患糖尿病的风险增加中风。本研究的基本假设是，偏瘫中风患者脂肪组织和骨骼肌中的关键炎症标志物（TRNa、脂联素）异常，骨骼肌胰岛素信号受损，全身胰岛素敏感性降低，并且这些因素是可以改变和改善的。通过对中风患者进行运动训练。本研究的目的如下： 1) 确定关键的全身性（TRNa 和脂联素循环水平）和组织（脂肪组织和骨骼肌）炎症（分泌、表达和细胞因子）是否与与年龄、性别、BMI、种族和危险因素匹配的非中风对照相比，慢性中风中受体 TNFR1、TNFR2、adipoR1、adipoR2 的表达）受到干扰，以及 6 个月的随机跑步机训练干预是否会改变中风中的这些炎症标志物患者; 2) 确定 6 个月的随机跑步机训练干预与拉伸控制相比，是否通过改变下游信号（AMPK、JNK、IRS1-Ser307、Akt 和 p-38 MAPK 磷酸化）和 GS 活性来改善中风患者的全身胰岛素敏感性偏瘫和非瘫痪腿部骨骼肌。为了实现这些目标，90 名年龄 55-75 岁、BMI 20-35 kg/m2 的受试者（n = 18 名对照者和 n = 72 名偏瘫中风患者）将接受腹部和臀部脂肪组织活检，以及基础和胰岛素刺激的股外侧肌检查。高胰岛素-正常血糖钳夹期间的肌肉活检。中风受试者将被分配到 6 个月的跑步机或教育/伸展控制干预中，使用一对二一随机化来阻止种族、性别和葡萄糖耐量状态。这项临床转化研究试验将临床结果带到实验室，以确定与年龄和危险因素匹配的非中风对照相比，中风中全身胰岛素抵抗的分子机制，以及跑步机训练是否能减少炎症并提高中风中的全身胰岛素敏感性。中风。直接测量脂肪组织和骨骼肌中的炎症调节剂将提供关于所选细胞因子是否对骨骼肌的胰岛素信号产生不利影响。此外，这一机制研究结果将为跑步机训练改善脂肪组织和骨骼肌中的炎症调节因子、改善骨骼肌中的胰岛素信号和作用以提高老年中风患者的胰岛素敏感性提供分子机制的第一个证据。这项研究将确定治疗中风幸存者胰岛素抵抗的策略，并为建议改变生活方式以减少炎症和改善中风代谢状况奠定生物学基础。