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: 7141154
• 负责人: ZIXI Jack CHENG
• 金额: $ 12.91万
• 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/7141154
• 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）：糖尿病和衰老通常与心血管疾病的发病率和严重程度增加有关。但是，我们对这些功能障碍背后的神经机制的理解阻碍了关于自主神经末端和心脏组织内电路的结构信息（大脑心脏连接）。对心脏的迷走神经的投影源自感官神经节，即nodose神经节和两个运动核，即Ambiguus（Na）核（Na）和传奇的背运动核（DMNX）。本应用的总体目标是确定由糖尿病，衰老或两者兼而有之的心脏迷走神经控制的功能缺陷，并确定对心脏神经回路的损害，特别是对迷走神经轴突对心脏的损害。特定心脏功能的迷走神经控制将在两种1型糖尿病的鼠模型中测量（经延展性蛋白酶治疗和转基因OVE 26小鼠）。在副交感系统内的迷走性心脏轴突和末端，谷氨酸能的传播以及氧气活性物种（ROS）将使用一系列技术进行质量和定量检查，这些技术将包括传统的神经追踪，包括神经性神经追踪，立体计数，立体计数，共同体显微镜，共介摄氏度，神经镜，多构造，多生成型，多层次，双重构成，多重构成，多重构造，多重构造，双重构成，多重构造，多重构成，多重构成，双重构成，多重生物学，双重构成，双重构成，多重构成，多重构成，综合构成综合性，多个互动式，多重构成群体群体群罗斯。这些解剖学发现将与生理反应一起评估，以增强我们对结构功能关系的理解。 AIM 1将评估与糖尿病相关的压力反射和迷走神经控制的衰减，以及对心脏和主动脉弓的迷走神经预测的相关结构变化，并检查是否相互作用糖尿病和衰老是否相互作用以诱导更严重的功能性和解剖学损害对传统心脏轴突的损害。 AIM 2将研究脑干内谷氨酸能传播的糖尿病和衰老相关的变化。 AIM 3将确定糖尿病和衰老小鼠副交感神经元中的ROS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性损害，总体而言，所提出的实验将提供独特的洞察力，以使其对长期糖尿病的心脏流失进行模糊流失的重塑。