Mechanisms modulating the maintenance of structural integrity in individual aging

描述（由申请人提供）：衰老的人类大脑中细微的变化，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晚发性神经退行性疾病的神经元功能障碍。目前，我们对这些过程及其后果的了解太少，无法利用这些知识设计治疗干预措施。我们研究秀丽隐杆线虫神经元老化的基本过程。在这种透明的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，我们仔细记录了秀丽隐杆线虫的一些神经元是如何随着动物变老而发生物理变化的。我们发现秀丽隐杆线虫与人类大脑老化一样，随着年龄的增长几乎没有神经元的损失。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；这些神经元的功能可能会减弱。我们可以用高倍解剖显微镜记录这种戏剧性的与年龄相关的树突重组，这有助于相对快速地分析活的、衰老的动物体内的单个神经元。确定成人神经系统维持其结构完整性的机制，并详细阐述与年龄相关的树突重组的鲜为人知的机制，对正常衰老和神经退行性疾病都具有相当重要的意义。我们将结合使用荧光报告和基因操作来解决三个目标：目标1是定义个体衰老神经元中蛋白质平衡破坏和树突重组的关系；目标2是定义个体衰老神经元中线粒体状态和年龄相关树突重组之间的关系。这项研究也将在描述自然环境下单个神经元中衰老线粒体群体的基本细胞生物学方面开辟新的领域。目的3是筛选候选基因集，以确定影响老化神经系统结构完整性维持的新因素。我们的研究应解决对成熟神经系统结构维持的基本生物学理解上的空白，并告知可能更好地维持衰老的人类神经系统完整性和功能的机制和干预措施。

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.