Gastrointestinal Tract Innervation: Patterns of Aging

描述(申请人提供)：在老年人中，胃肠道(GI)疾病很常见，通常会并发或合并其他疾病，并可能使人虚弱。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或肠道神经丛中神经元的急剧丧失(~40%-50%)有关。然而，过去的研究非常有限，几乎完全集中在确定损失是否发生上。目前对明确潜在机制、建立因果关系或制定合理的治疗干预措施知之甚少。更具体地说，关于胃肠道区域受损的信息太少，关于死亡或存活的神经元的神经化学表型，以及溶解的时间模式的信息太少。神经科学对衰老胃肠道的研究主要集中在少数几个肠道区域的肌间神经丛，而忽略了某些器官(如胃)、某些肠道成分(如粘膜下神经丛)以及连接肠道与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)。本提案的长期目标，统一了它的四个具体目标，是描述胃肠道神经元老化的区域、时间和神经化学模式。目标1将明确整个肠道内经历与年龄相关的神经退变的肠神经元的神经化学表型。还将描述这种损失在整个生命周期中的演变。目标2将分析与年龄相关的胃肠道外源性神经支配的轴突病变，并确定这些病理发展的时间模式。目标3将把与衰老相关的胃肠动力和营养物质处理的变化与目标1和目标2所描述的不同的特定神经病变联系起来。目标4将开始评估两个特别有希望的假说，确定神经元丢失和衰老轴突病变的细胞机制。这四个目标将通过一系列免疫组织化学方案、顺行追踪技术和使用最近开发的时空映射算法的肠道运动模式的功能分析来解决。这些分析将主要利用国家老龄研究所建立的衰老动物模型进行。综上所述，关于胃肠道老化的拟议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。公共卫生相关性对胃肠道神经损伤随年龄增长的空间、时间和神经化学模式的拟议理解将为临床干预或管理一些影响老年人食欲、摄取、消化和运动以及最终影响营养和健康的动态平衡和消化障碍的合理策略提供亟需的基础。

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.