Mechanisms modulating the maintenance of structural integrity in individual aging

描述（由申请人提供）：衰老人脑中的细微变化，如神经元发芽和重组，被认为是认知能力下降的基础，并可能促进阿尔茨海默氏症和其他迟发性神经退行性疾病中的神经元功能障碍。目前，我们对这些过程及其后果了解得太少，无法利用这些知识来设计治疗干预。我们在C.优雅在这个透明的959细胞动物中，我们可以直接观察到单个荧光标记的神经元，以及荧光标记的蛋白质聚集体和线粒体。最近，我们仔细记录了一些C。线虫的神经元随着动物的衰老而发生物理变化。我们发现，就像人类大脑老化一样，C.优雅的年龄。然而，随着年龄的增长，某些类型的神经元表现出戏剧性的新分支和生长;这些神经元可能已经减弱了功能。我们可以使用高倍解剖显微镜对这种与年龄相关的树突状结构进行评分，这有助于对活体衰老动物中的单个神经元进行相对快速的分析。确定成年神经系统维持其结构完整性的机制，并详细阐述年龄相关树突重建的机制，对正常衰老和神经退行性疾病都具有相当重要的意义。我们将结合联合收割机使用的荧光报告基因操作，以解决三个目标：目的1是确定蛋白质稳态破坏和树突状细胞在个别老化神经元的重建的关系。目的2是确定线粒体状态和年龄相关的树突状细胞在个别老化神经元的重建之间的关系。这项研究还将在表征自然环境中单个神经元中老化线粒体群体的基本细胞生物学方面开辟新天地。目的3是筛选候选基因集，以确定影响衰老神经系统结构完整性维持的新因素。我们的研究应该解决在理解基础生物学方面的差距，通过这些生物学，结构维持在成熟的神经系统中完成，并提供有关机制和干预措施的信息，这些机制和干预措施可以更好地维持衰老的人类神经系统的完整性和功能。

DESCRIPTION (provided by applicant): Subtle changes in the aging human brain, such as neuronal sprouting and restructuring, are thought to underlie cognitive decline and may promote neuronal dysfunction in Alzheimer's and other late-onset neurodegenerative disease. Currently we understand too little of these processes and their consequences to harness knowledge for design of therapeutic intervention. We study fundamental processes relevant to neuronal aging in C. elegans. In this transparent 959-celled animal, we can directly observe individual fluorescently labeled neurons, as well as fluorescently tagged protein aggregates and mitochondria. Recently, we carefully documented how some C. elegans neurons physically change as animals grow old. We find that like human brain aging, there is little neuron loss as C. elegans ages. However, some types of neurons exhibit dramatic novel branching and outgrowth with age; such neurons might have diminished function. We can score this dramatic age-associated dendritic restructuring using a high-magnification dissecting microscope, which facilitates relatively rapid analysis of individual neurons within live, aging animals. Defining th mechanisms by which adult nervous systems maintain their structural integrity and elaborating on the poorly understood mechanisms of age-associated dendritic restructuring is of considerable importance to both normal aging and neurodegenerative disease. We will combine use of fluorescent reporters with genetic manipulations to address three aims: Aim 1 is to define the relationship of proteostasis disruption and dendritic restructuring in individual aging neurons Aim 2 is to define the relationship between mitochondrial status and age-associated dendritic restructuring in individual aging neurons. This study will also break new ground in characterizing the basic cell biology of the aging mitochondrial populations in individual neurons in native context. Aim 3 is to screen candidate gene sets to identify novel factors that influence the maintenance of structural integrity of the aging nervous system. Our studies should address gaps in understanding of the basic biology by which structural maintenance is accomplished in a mature nervous system and inform on mechanisms and interventions that may better maintain the integrity and function of the aging human nervous system.