Gastrointestinal Tract Innervation: Patterns of Aging

描述（由申请人提供）：在老年人中，胃肠道（GI）疾病很常见，通常使其他疾病复杂化或由其他疾病复杂化，并且可能使人衰弱。过去十年的研究已经确定，衰老相关的GI疾病与消化道自主神经丛或肠神经丛中神经元的急剧损失（约40 - 50%）相关。然而，过去的研究非常有限，几乎完全集中在确定损失的发生上。目前所知太少，无法详细说明潜在的机制，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区域受损、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。衰老胃肠道的神经科学主要集中在少数肠道区域的肌间神经丛，而忽略了一些器官（例如，胃），一些肠元件（例如，粘膜下神经丛），以及广泛的外在运动和感觉神经支配（例如，迷走神经和交感神经投射），其将肠道连接到中枢神经系统。本提案的长期目标，统一了其四个具体目标，是描述胃肠道神经元老化的区域，时间和神经化学模式。目的1将详细说明整个肠道发生年龄相关神经退行性变的肠神经元的神经化学表型。还将描述这种损失在整个寿命期间的演变。目的2将分析年龄相关的神经轴突病变的外在神经支配的胃肠道，并确定时间模式，这些病理发展。目的3将与年龄相关的胃肠道运动和营养处理的变化与目的1和2中表征的不同特异性神经病变相关联。目标4将开始评估两个特别有前途的假说，确定细胞机制的神经元损失和轴突病变的老化。这四个目标将使用一组免疫组化协议，顺行追踪技术，并采用最近开发的时空映射算法的肠道动力模式的功能测定来解决。这些分析将主要使用国家老龄化研究所建立的衰老动物模型进行。总之，对胃肠道老化的拟议观察将指定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。 公共卫生相关性拟议的理解的空间，时间和神经化学模式的神经损失在胃肠道与老化将提供一个急需的基础，合理的策略，临床干预或管理的一些稳态和消化系统疾病，影响食欲，摄取，消化，运动，以及最终，营养和健康，在老年人。

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.