Role of Sterols and Insulin in Cardiac Autonomic Response

甾醇和胰岛素在心脏自主反应中的作用

基本信息

批准号：
8098062
负责人：
Jonas Bernard Galper
金额：
$ 39.75万
依托单位：
TUFTS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-08-01 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8098062
关键词：
3-Phosphoinositide Dependent Protein Kinase-1 Acetylcholine Apoptosis Arrhythmia Autonomic Dysfunction Binding Binding Proteins Body Patterning Brain Cardiac Cell physiology Cells Chemicals Cholesterol Cholesterol Homeostasis Chronic Code Complications of Diabetes Mellitus Coupled Development Diabetes Mellitus Diabetic Autonomic Neuropathy Diabetic mouse Disease Dominant-Negative Mutation Energy Metabolism Enzymes Fatty Acids Functional disorder GIRK1 subunit, G protein-coupled inwardly-rectifying potassium channel GIRK4 subunit, G protein-coupled inwardly-rectifying potassium channel GTP-Binding Proteins Gene Expression Genes Genetic Transcription Glycogen (Starch) Synthase Glycogen Synthase Kinase 3 Glycogen Synthase Kinases Glycolysis Goals Heart Heart Atrium Heart Rate Heterotrimeric GTP-Binding Proteins Hyperactive behavior Impairment Incidence Inflammation Insulin Insulin Signaling Pathway Insulin-Like Growth-Factor Binding Protein 1 Knock-out Knockout Mice Lipids Malignant Neoplasms Mediating Mediator of activation protein Membrane Messenger RNA Metabolic Modeling Mus Muscarinic M2 Receptor Muscarinics Muscle Cells Myocardium Neurodegenerative Disorders Neurons Pathogenesis Pathway interactions Patients Phosphatidylinositols Phosphorylation Phosphotransferases Play Point Mutation Population Potassium Channel Prevention Promoter Regions Protein-Serine-Threonine Kinases Proto-Oncogene Proteins c-akt Receptor Activation Recording of previous events Regulation Regulatory Element Role SRE-1 binding protein Signal Transduction Sterols Structure of parasympathetic ganglion Sudden Death Supporting Cell Testing Therapeutic Agents Time Ubiquitination Viral atrioventricular node cardiogenesis chronotropic diabetic diabetic patient drug testing efficacy testing follow-up inhibitor/antagonist inward rectifier potassium channel new therapeutic target non-diabetic novel therapeutics overexpression promoter protein expression public health relevance research study response therapeutic target transcription factor type I diabetic

项目摘要

DESCRIPTION (provided by applicant: Diabetic Autonomic Neuropathy is a severe complication of diabetes. More than 50% of patients with a 10-year history of diabetes demonstrate an impaired response of the heart to parasympathetic stimulation and a resulting sympathovagal imbalance. Furthermore, there is a marked increase in the incidence of sudden death in diabetics which may be associated, at least in part, with a decrease in parasympathetic responsiveness of the heart. Parasympathetic stimulation of the heart involves acetylcholine binding to M2 muscarinic receptor, and activation of the G protein-activated inward rectifier K+ channel, (GIRK1)2/(GIRK4)2 which is responsible for IKACh, the hyperpolarizing K+ current that causes a hyperpolarization of the cardiac membrane and a decrease in heart rate. Sterol regulatory element binding proteins (SREBPs) are the transcription factors that regulate genes involved in fatty acid and cholesterol synthesis. Glycogen synthase kinase 3beta (GSK3beta), which was found to be a key regulatory component of the insulin-signaling pathway, is constitutively active and is inhibited by Akt-mediated phosphorylation in response to insulin. It has been suggested that GSK3beta plays a role in the ubiquitination and degradation of SREBPs. Insulin has been shown to increase SREBP-1 levels. We previously demonstrated that the Akita diabetic mouse, which has a point mutation in the pro-insulin gene (ins2), demonstrates a markedly decreased response to parasympathetic stimulation of the heart. Using this mouse we previously showed that G1i2 and GIRK1 are up-regulated by SREBP-1 and that the hypoinsulinemia in the diabetic mouse resulted in decreased expression of GIRK1 and a decrease in IKACh. Adenoviral expression of SREPBP-1 reversed this impairment of IKACh in atrial myocytes from the Akita mouse. Akt/GSK3beta are important mediators of the metabolic effects of insulin. In this application will test 4 major hypotheses: 1) that GSK3beta activity in the diabetic heart is increased and that this is associated with decreased levels of SREBP, GIRK1 and GIRK4. 2) that GSK3 regulates the expression of GIRK1 and GIRK4 at the level of transcription via an effect on the turnover of SRBP-1, 3) that chemical inhibitors of GSK3 and overexpression of a DN-GSK3 reverse the impairment of IKACh in atrial myocytes from Akita mice and stimulates the expression of GIRK1 and GIRK4 in atrial myocytes form Akita mice and that treatment of mice with an inhibitor of GSK3 reverses parasympathetic dysfunction in these mice and 4) that crossing a mouse with a conditional cardiac specific KO of GSK3 with the Akita type I diabetic mouse protects the mouse from developing parasympathetic dysfunction and that this effect is reversed by the expression of a DA-GSK3 in the atria of these mice. These studies should not only identify a new pathway and potential therapeutic target for the pathogenesis and treatment of diabetic autonomic neuropathy, but test the efficacy of GSK3 inhibitors in the treatment and prevention of this devastating complication of diabetes. PUBLIC HEALTH RELEVANCE: The inability of the brain to regulate the rate and force of beating of the heart is a major complication of diabetes which has been associated with sudden death in the diabetic population. Glycogen Synthase Kinase (GSK3) is a molecule that is normally controlled by insulin; here we will determine whether the insulin deficiency in the Type I diabetic mice results in uncontrolled GSK3 and whether this increase in GSK3 results in the loss of the ability of the brain to control the heart beat. We will test drugs that reverse the increased GSK3 in the diabetic heart for their ability to restore the response of the heart to signals from the brain; these studies have the potential of developing a new therapeutic target for the treatment and prevention of this debilitating complication of diabetes.

描述（由申请人提供：糖尿病自主神经病是糖尿病的严重并发症。超过50％的糖尿病病史的患者中有50％以上表现出心脏对副交感神经刺激的反应受损，并且副交感神经不平衡的反应是疾病的出现。在疾病中可能会出现显着的疾病，至少在疾病中的出现可能会导致疾病的出现，至少在疾病中疾病的发病率会导致疾病的发病率相关。心脏的副交感神经反应性涉及乙酰胆碱与M2毒蕈碱受体的结合，并激活G蛋白激活的内向整流器K+通道（GIRK1）2/（girk1）2/（girk4）固醇调节元素结合蛋白（SREBPS）是调节脂肪酸和胆固醇合成的基因的转录因子，糖原合酶激酶3Beta（GSK3BETA）被发现是由胰岛素 - 信号plandy的关键调节性的，这是胰岛素 - 信号的关键。胰岛素。有人提出，GSK3Beta在SREBPS的泛素化和降解中起作用。胰岛素已被证明会增加SREBP-1水平。我们先前证明，在胰岛素基因中具有点突变的Akita糖尿病小鼠（INS2）表现出对心脏副交感神经刺激的反应明显下降。使用此小鼠，我们先前表明G1I2和GIRK1被SREBP-1上调，并且糖尿病小鼠中的低胰岛素血症导致GIRK1表达降低，IKACH降低。 SREPBP-1的腺病毒表达逆转了Akita小鼠中心肌细胞中Ikach的这种损害。 AKT/GSK3BETA是胰岛素代谢作用的重要介体。在此应用中，将检验4个主要假设：1）糖尿病心脏中GSK3BETA活性增加，这与SREBP，GIRK1和GIRK4的水平降低有关。 2）GSK3通过对SRBP-1的周转效果的影响，调节GIRK1和GIRK4在转录水平上的表达形成akita小鼠和用GSK3抑制剂对小鼠进行处理，在这些小鼠中逆转了副交感神经功能障碍和4）4）与Akita I型糖尿病小鼠的有条件的心脏特异性KO跨过小鼠，使小鼠免受副交感神经功能障碍的效果，并表达了这些效果，并表达了这些效果。这些研究不仅应确定新的途径和潜在的治疗靶标，用于糖尿病自主神经病的发病机理和治疗，而且测试了GSK3抑制剂在治疗和预防这种破坏性糖尿病并发症方面的疗效。公共卫生相关性：大脑无法调节心脏跳动的速度和力量是糖尿病的主要并发症，这与糖尿病人群中的猝死有关。糖原合酶激酶（GSK3）是通常由胰岛素控制的分子。在这里，我们将确定I型糖尿病小鼠中的胰岛素缺乏会导致不受控制的GSK3以及GSK3的增加是否导致大脑控制心脏跳动的能力的丧失。我们将测试糖尿病心脏中GSK3增加的药物，因为它们能够恢复心脏对来自大脑信号的反应的能力。这些研究具有开发新的治疗靶标，以治疗和预防这种使糖尿病的衰弱并发症。