Mechanisms of Aging in the Olfactory System

描述（申请人提供）：衰老对嗅觉功能有深远的影响。嗅觉敏感度和辨别气味的能力都会下降，不仅会导致生活质量下降，还会导致严重的营养不足。此外，阿尔茨海默氏症和帕金森氏症，以及其他疾病，都表现出早期的嗅觉缺陷和病理。尽管有这些重要的观察结果，但在研究嗅觉系统衰老的细胞和分子后遗症的动物模型的发展方面做得很少。在这里，我们提出了一系列协调的研究，从嗅觉上皮开始，在那里气味被检测到，并通过嗅球和嗅皮层，两个中心区域的气味处理进行。利用四个参与实验室的优势，我们采用先进的分子、细胞、解剖、电生理和计算分析。在项目1中，微阵列和生理实验将评估嗅上皮和嗅球的状态。在项目2中，分子遗传学方法将用于评估嗅觉感觉神经元的周转、气味受体的表达以及嗅觉感觉神经元向球茎的轴突投射。在项目3突触组织和平衡的主要传入和局部回路突触将被检查。最后，在项目4中，将研究嗅觉皮层中分子定义的气味通路的表示。在每个项目中，我们使用相同的年龄，我们将共享数据和试剂。虽然每个项目都有自己的特定目标，但PPG作为一个整体是在一个共同的假设下团结起来的，即理解衰老嗅觉缺陷的本质需要对衰老嗅觉系统的分子和细胞生物学有全面的了解。是什么让这个PPG比它的简单部分的总和更伟大的是我们以协调的方式分析嗅觉通路的完整连续体的能力。因此，我们将得出的不是嗅觉系统的特定方面或水平如何在衰老中受到影响的孤立观点，而是嗅觉系统如何作为一个整体受到损害。

DESCRIPTION (provided by applicant): Aging has profound effects on olfactory function. Olfactory sensitivity and the ability to discriminate among odors both decline, leading not only to decrements in the quality of life, but also to serious nutritional deficits. Moreover, both Alzheimer's and Parkinson's disease, among others, show early onset of olfactory deficits and pathology. Despite these important observations, little has been done in the development of animal models for studying the cellular and molecular sequelae of aging in the olfactory system. Here we propose a coordinated series of studies that begin in the olfactory epithelium, where odors are detected, and proceed through the olfactory bulb and olfactory cortex, the two central areas of odor processing. Drawing on the strengths of each of the four participating laboratories, we employ advanced molecular, cellular, anatomical, electrophysiological and computational analyses. In Project 1 microarrays and physiological experiments will assess the status of the olfactory epithelium and bulb. In Project 2 molecular genetic approaches will be used to evaluate turnover of olfactory sensory neurons, expression of odorant receptors, and axonal projections of olfactory sensory neurons to the bulb. In Project 3 the synaptic organization and the balance of primary afferent and local circuit synapses will be examined. Finally, in Project 4 the representation of molecularly-defined odor pathways in olfactory cortex will be studied. In each project we use the same ages and we will share data and reagents. While each project has its own specific aims, the PPG as a whole is united under the common hypothesis that understanding the nature of olfactory deficits in aging requires a comprehensive knowledge of the molecular and cellular biology of the aging olfactory system. What makes this PPG greater than the simple sum of its parts is our ability to analyze the full continuum of the olfactory pathway in a coordinated manner. We will thus emerge not with isolated views of how particular aspects or levels of the olfactory system are affected in aging, but how the olfactory system is impaired as a whole.