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：
8066005
负责人：
CHARLENE E HAFER-MACKO
金额：
$ 48.16万
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/8066005
关键词：
3 year old 5&apos -AMP-activated protein kinase Abdomen Activities of Daily Living Acute-Phase Proteins Adipocytes Adipose tissue Adult Affect Age Aging Anti-Inflammatory Agents Anti-inflammatory Behavior Therapy 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 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 Inflammation Mediators Inflammatory Insulin Insulin Resistance Interleukins Intervention Intramuscular Knock-out Knowledge Lead Leg Limb structure Link Measurement Mediating Medical Metabolic Metabolic syndrome Mitogen-Activated Protein Kinases Modeling Molecular Muscle Muscle function Neurologic Non-Insulin-Dependent Diabetes Mellitus 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 Stretching Stroke Surrogate Markers Survivors TNFRSF1A gene Thigh structure Tissues Training Transcript Translational Research Tumor Necrosis Factor Receptor Tumor Necrosis Factor-alpha 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 high risk human MAPK14 protein impaired glucose tolerance improved inflammatory marker 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 vastus lateralis 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）：全身性炎症在动脉粥样硬化疾病以及心血管和脑血管事件，胰岛素抵抗以及2型糖尿病的发展中起关键作用。胰岛素耐药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感的脂肪因子）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发展。此外，高胰岛素血症患病率很高，个体患糖尿病的风险增加中风。这项研究的基本假设是，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，全身性胰岛素敏感性降低了偏瘫患者的敏感性，这些因素和这些因素可改善这些因素，并通过锻炼患者进行了运动培训。这项研究的目的是：1）确定关键系统性（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）是否是否与年龄，性别，性别，BMI，种族和风险因素相比，受体TNFR1，TNFR2，ADIPOR1，ADIPOR1，ADIPOR2表达）在慢性中风中受到干扰。和2）确定与中风患者的拉伸对照相比，通过改变下游信号（AMPK，JNK，IRS1- SER307，AKT和P-38 MAPK磷酸化）和Hemiparecetic and GS活性，与中风患者的拉伸对照相比，与中风患者的拉伸对照相比，是否有6个月的随机跑步机训练干预是否可以提高全身性胰岛素敏感性。为了实现这些目标，有90名受试者（n = 18个对照和n = 72个偏瘫患者），年龄为55-75岁，BMI 20-35 kg/m2将接受腹部和谷物脂肪组织活检，以及基础和胰岛素刺激的后期巨型肌肉生物的基础和胰岛素刺激性的肌肉生物素。中风受试者将使用对种族，性别和葡萄糖耐受状态的一二个随机分配为6个月的跑步机或教育/伸展控制干预措施。与年龄和风险因素匹配的非冲程训练相比，这项临床翻译研究试验从诊所到板凳的生理结果从诊所到板凳，以确定中风中全身性胰岛素抵抗的分子机制，以及跑步机训练是否会减少炎症并改善Stroke的全身胰岛素敏感性。直接测量脂肪组织和骨骼肌中的炎症调节剂将提供有关选定细胞因子的新信息不利影响骨骼肌处的胰岛素信号传导。此外，机械性发现将提供分子机制的第一个证据，跑步机训练可以改善脂肪组织和骨骼肌的炎症调节剂，并改善骨骼肌的胰岛素信号传导和作用，以提高较老的中风患者的胰岛素敏感性。这项研究将确定一种治疗中风幸存者中胰岛素抵抗的策略，并建立推荐生活方式修改以减少炎症并改善中风中代谢特征的生物学基础。