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Cardiac Neuropathy in Type 1 Diabetic and Aging

1 型糖尿病患者的心脏神经病变与衰老

基本信息

批准号：
7279129
负责人：
ZIXI Jack CHENG
金额：
$ 33.66万
依托单位：
UNIVERSITY OF CENTRAL FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-09-30 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7279129
关键词：
AMPA Receptors Acute Age Aging Antioxidants Appendix Area Arrhythmia Attenuated Axon Baroreflex Biological Assay Brain Brain Stem Cardiac Cardiac Myocytes Cardiomyopathies Cardiovascular Diseases Cardiovascular system Cell Nucleus Chronic Confocal Microscopy Count Development Diabetes Mellitus Diabetic Neuropathies Diabetic mouse Disease Elderly Functional disorder Ganglia Glutamate Receptor Glutamates Goals Heart Heart Rate Heart failure High Prevalence Hypertension Immunochemistry Immunohistochemistry Incidence Injection of therapeutic agent Insulin-Dependent Diabetes Mellitus Lasers Lesion Life Measurement Measures Microinjections Microscopy Modeling Modification Molecular Morbidity - disease rate Motor Mus Myxoid cyst N-Methylaspartate Nerve Nerve Fibers Neurons Neuropathy Nodose Ganglion Oryctolagus cuniculus Parasympathetic Nervous System Patients Physiological Pressoreceptors Presynaptic Terminals Process Production Proteins Protocols documentation Rattus Reactive Oxygen Species Reflex action Research Personnel Risk Risk Factors Role Scanning Sensory Ganglia Severities Site Staining method Stains Streptozocin Structure Structure-Activity Relationship Sudden Death System Techniques Testing Tissues Transgenic Mice Transgenic Organisms Vitamin E aortic arch attenuation autonomic nerve brain tissue diabetic dorsal motor nucleus improved insight mortality mouse model neural circuit neuromechanism novel novel strategies nucleus ambiguus outcome forecast prevent programs receptor expression relating to nervous system research study response transmission process type I diabetic

项目摘要

DESCRIPTION (provided by applicant): Diabetes mellitus and aging are commonly associated with increased incidence and severity of cardiovascular diseases. However, our understanding of the neural mechanisms underlying these dysfunctions is impeded by a lack of structural information on autonomic nerve terminals and the circuitry within the cardiac tissues (brain-heart connections). Vagal projections to the heart originate from a sensory ganglion, i.e., the nodose ganglion, and the two motor nuclei, i.e., the nucleus ambiguus (NA) and the dorsal motor nucleus of the vagus (DmnX). The overall goal of the present application is to determine the functional deficits of the vagal control of the heart induced by diabetes, aging or both, and to identify the damage to the cardiac neural circuitry, specifically to the vagal axonal projections to the heart. Vagal control of particular cardiac functions will be measured in two murine models of type 1 diabetes (strepozotocin-treated and transgenic OVE 26 mice). The vagal cardiac axons and terminals, glutamatergic transmission, and oxygen reactive species (ROS) within the parasympathetic system will be examined qualitatively and quantitatively using a battery of techniques that will include anterograde neural tracing, stereological counting, confocal microscopy, Neurolucida digitization, multichannel injections, dual immunohistochemistry, and intercellular measurement of ROS. These anatomical findings will be assessed in conjunction with physiological responses to enhance our understanding of structure-function relationships. Aim 1 will assess diabetes-associated attenuation of baroreflex and vagal control of the heart, and the associated structural changes of vagal projections to the heart and aortic arch, and examine whether diabetes and aging interact to induce more severe functional and anatomical damage to the vagal cardiac axons. Aim 2 will study diabetes and aging-associated changes in glutamatergic transmission within the brainstem. Aim 3 will determine ROS productions in parasympathetic neurons in diabetic and aging mice, and study whether chronic antioxidant treatment may reduce/prevent cardiovascular dysfunctions and structural damages, Collectively, the proposed experiments will provide unique insights into the remodeling of vagal outflow to cardiac tissues following long-term diabetes.

描述（由申请人提供）：糖尿病和衰老通常与心血管疾病的发病率和严重程度增加有关。然而，由于缺乏自主神经末梢和心脏组织内电路（脑-心连接）的结构信息，我们对这些功能障碍背后的神经机制的理解受到阻碍。迷走神经向心脏的投射源自感觉神经节（即结状神经节）和两个运动核，即迷走核（NA）和迷走神经背运动核（DmnX）。本申请的总体目标是确定由糖尿病、衰老或两者引起的心脏迷走神经控制的功能缺陷，并识别对心脏神经回路的损伤，特别是对心脏的迷走神经轴突投射的损伤。将在两种 1 型糖尿病小鼠模型（链脲佐菌素治疗的转基因 OVE 26 小鼠）中测量迷走神经对特定心脏功能的控制。将使用一系列技术对副交感神经系统内的迷走神经心脏轴突和末端、谷氨酸传输和氧反应性物质（ROS）进行定性和定量检查，这些技术包括顺行神经示踪、体视计数、共聚焦显微镜、Neurolucida数字化、多通道注射、双重免疫组织化学和细胞间测量活性氧。这些解剖学发现将结合生理反应进行评估，以增强我们对结构功能关系的理解。目标 1 将评估与糖尿病相关的心脏压力反射和迷走神经控制的减弱，以及迷走神经投射到心脏和主动脉弓的相关结构变化，并检查糖尿病和衰老是否相互作用，从而对迷走神经心脏轴突造成更严重的功能和解剖损伤。目标 2 将研究糖尿病和与衰老相关的脑干内谷氨酸传输的变化。目标 3 将确定糖尿病和衰老小鼠副交感神经元中 ROS 的产生，并研究长期抗氧化治疗是否可以减少/预防心血管功能障碍和结构损伤。总的来说，所提出的实验将为长期糖尿病后迷走神经流出心脏组织的重塑提供独特的见解。