Gastrointestinal Tract Innervation: Patterns of Aging

描述（由申请人提供）：在老年人中，胃肠道（GI）疾病是常见的，通常是合并或合并其他疾病，并可能使人衰弱。过去十年的研究已经证实，与衰老相关的胃肠道疾病与消化道自主神经丛或肠道神经丛中神经元的显著损失（约40 - 50%）有关。然而，过去的研究非常有限，并且几乎完全集中在确定损失的发生上。目前所知太少，无法明确潜在的机制，建立因果关系，或制定合理的治疗干预措施。更具体地说，关于哪些GI区域受到损害，关于死亡或存活神经元的神经化学表型，以及关于溶解的时间模式的信息太少。老化胃肠道的神经科学主要集中在少数肠道区域的肌肠神经丛，而忽略了一些器官（如胃），一些肠道成分（如粘膜下神经丛），以及连接肠道和中枢神经系统的广泛的外源性运动和感觉神经支配（如迷走神经和交感神经投射）。目前的建议的长期目标，它统一了它的四个具体目标，是表征区域，时间和神经化学模式的神经元老化在胃肠道。目的1将明确整个肠道中经历与年龄相关的神经变性的肠神经元的神经化学表型。这些损失在生命周期中的演变也将被描绘出来。目的2将分析年龄相关的胃肠道外神经支配轴突病，并确定这些病理发展的时间模式。目的3将胃肠道运动和营养处理的衰老相关变化与目的1和目的2中所描述的不同特定神经病变联系起来。目的4将开始评估两个特别有希望的假设，确定神经元损失和衰老的轴突病的细胞机制。这四个目标将使用一系列免疫组织化学方案、顺行追踪技术和采用最近开发的时空映射算法的肠道运动模式功能分析来解决。这些分析将主要通过国家衰老研究所建立的衰老动物模型来完成。综上所述，对胃肠道衰老的观察将明确治疗干预应针对的脆弱区域、神经元表型、时间点和细胞过程。随着年龄的增长，对胃肠道神经损失的空间、时间和神经化学模式的理解将为临床干预或管理一些影响老年人食欲、摄入、消化和运动以及最终影响营养和健康的稳态和消化系统疾病提供急需的合理策略基础。

DESCRIPTION (provided by applicant): In the elderly, gastrointestinal (GI) disorders are common, often either complicate or are complicated by other diseases, and can be debilitating. Research over the last decade has established that aging-related GI disorders are correlated with dramatic losses (~40 - 50%) of neurons in the autonomic, or enteric, plexuses of the digestive tract. The past research is very limited, however, and has been focused almost exclusively on establishing that losses occur. Too little is presently known to specify underlying mechanisms, to establish causal relationships, or to formulate rational therapeutic interventions. More specifically, too little information is available on which GI regions are compromised, on the neurochemical phenotypes of either the neurons that die or those that survive, and on the temporal patterning of the dissolution. The neuroscience of the aging GI tract has largely focused on the myenteric plexus in a few intestinal regions, while ignoring some organs (e.g., the stomach), some enteric elements (e.g., the submucosal plexus), and the extensive extrinsic motor and sensory innervation (e.g., vagal and sympathetic projections) that links the gut to the central nervous system. The present proposal's long-term objective, which unifies its four specific aims, is to characterize the regional, temporal and neurochemical patterns of neuronal aging in the GI tract. Aim 1 will specify the neurochemical phenotypes of enteric neurons throughout the gut that undergo age-related neurodegeneration. The evolution of such losses over the lifespan will also be delineated. Aim 2 will analyze age-related axonopathies of the extrinsic innervation of the GI tract and determine the temporal patterns by which those pathologies develop. Aim 3 will correlate aging-associated changes in GI motility and nutrient handling with the different specific neuropathies characterized in Aims 1 and 2. Aim 4 will begin to evaluate two particularly promising hypotheses identifying cellular mechanisms underlying the neuronal losses and axonopathies of aging. The four aims will be addressed using a battery of immunohistochemical protocols, anterograde tracing techniques, and functional assays of gut motility patterns employing recently developed spatio-temporal mapping algorithms. These analyses will be done primarily with animal models of aging established by the National Institute on Aging. Taken together, the proposed observations on the aging the GI tract will specify the vulnerable regions, neuronal phenotypes, timepoints, and cellular processes to which therapeutic interventions should be targeted. PUBLIC HEALTH RELEVANCE The proposed understanding of the spatial, temporal and neurochemical patterns of neural losses in the GI tract with aging will provide a much-needed foundation for rational strategies for clinical interventions or management of some of the homeostatic and digestive disorders that affect appetite, ingestion, digestion, and motility, as well ultimately, nutrition and health, in the elderly.