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

• 批准号: 7123381
• 负责人: ZIXI Jack CHENG
• 金额: $ 34.67万
• 依托单位: UNIVERSITY OF CENTRAL FLORIDA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7123381
• 关键词: AMPA receptors; NMDA receptors; aging; antioxidants; aorta; baroreceptors; baroreflex; brain stem; confocal scanning microscopy; diabetic neuropathy; free radical oxygen; ganglions; genetically modified animals; heart innervation; immunocytochemistry; insulin dependent diabetes mellitus; laboratory mouse; microinjections; neuroanatomy; neuropathology; neurophysiology; neuroregulation; parasympathetic nervous system; phenylephrine; receptor expression; streptozotocin; tocopherols; vagus nerve

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)：糖尿病和老龄化通常与心血管疾病的发病率和严重性增加有关。然而，由于缺乏关于自主神经末梢和心脏组织内回路(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了阻碍。迷走神经向心脏的投射来自感觉神经节(即结状节)和两个运动核团，即疑核(NA)和迷走神经背侧运动核(DmnX)。本申请的总体目标是确定糖尿病、衰老或两者兼而有之引起的心脏迷走神经控制的功能缺陷，并确定心脏神经回路的损害，特别是迷走神经向心脏的轴突投射。将在两种1型糖尿病小鼠模型(链脲佐菌素治疗和转基因Ove26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系统内迷走神经轴突和终末、谷氨酸能传递和氧活性物质(ROS)进行定性和定量检测，这些技术包括顺行神经示踪、体视学计数、共聚焦显微镜、神经透明带数字化、多通道注射、双重免疫组织化学和ROS的细胞间测量。这些解剖学发现将结合生理反应进行评估，以加强我们对结构-功能关系的理解。目的1评估糖尿病对心脏压力感受器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，并研究糖尿病和衰老是否相互作用，导致迷走神经心脏轴突受到更严重的功能和解剖损害。目标2将研究糖尿病和衰老相关的脑干内谷氨酸能传递的变化。目的3将测定糖尿病和衰老小鼠副交感神经元中ROS的产生，并研究慢性抗氧化剂治疗是否可以减少/预防心血管功能障碍和结构损伤，总之，拟议的实验将为长期糖尿病后迷走神经流出到心脏组织的重塑提供独特的见解。