The Olfactory Neural Circuit as a systems Level Model of Neurodegenerative Diseas

描述(由申请人提供) 摘要：神经退行性疾病将日益困扰我们的社会，因为现代医学增加了人们达到第七、第八和九十岁的人数。这些病理过程侵蚀了易感神经回路的功能完整性。在识别这些疾病过程中的突变和基因产物方面取得了很大进展，特别是早发性阿尔茨海默病(AD)和帕金森病(PD)。虽然这些发现导致了这些疾病的小鼠模型的发展，但在系统层面上，人们对这些疾病基因如何影响特定神经回路的功能知之甚少。我们已经开发了一种实验方法来阐明在单个哺乳动物神经回路中导致神经退行性疾病的基因的作用。利用小鼠遗传学，我们以有条件的方式在初级嗅觉神经元中特异地表达了AD基因。对这一模型的表征揭示了一组小鼠嗅觉神经元，在存在这种AD基因的情况下，它们经历了增强的细胞死亡和轴突错误定位的非细胞自主方式。在这项提案中，我们概述了一系列研究，以扩展我们对这一小鼠模型的分析：1.使用多光子显微镜进行体内纵向功能成像；2.原代嗅觉神经元培养，可用于高通量筛选逆转细胞死亡表型的分子。这个屏幕上的点击可以通过鼻内传递到嗅觉上皮来在小鼠模型中快速测试。此外，我们建议将这一实验方法扩展到与其他神经退行性疾病相关的基因，如帕金森病。在系统水平上阐明这些疾病基因的作用，并从我们的神经电路小鼠模型中获得新的功能和细胞结果，并在该模型系统中表征其他神经退行性疾病基因，有望有助于开发有效的治疗方法。 公共卫生相关性：神经退行性疾病，特别是阿尔茨海默病，目前对公共健康有巨大的影响；在美国，估计每年给我们的社会造成的损失超过1000亿美元。此外，随着婴儿潮一代进入第七、第八和九十岁，这种发病率预计将在未来30年内翻两番。为这些疾病制定有效的治疗方法和/或预防措施，将减轻遭受这些悲剧性疾病之苦的个人的生活质量损失，并减轻我们社会的经济影响。该项目有望有助于我们对这些疾病的了解，并有助于开发有效的治疗干预措施。

DESCRIPTION (Provided by the applicant) Abstract: Neurodegenerative disease will increasingly plague our society as modern medicine augments the number of people reaching their seventh, eighth, and ninth decades. These pathological processes erode the functional integrity of susceptible neural circuits. Much progress has been gained in identifying mutations and gene products that underlie these disease processes, particularly early onset Alzheimer's disease (AD) and Parkinson's disease (PD). While these findings have lead to the development of mouse models of these diseases, little is known at the systems level about how these disease genes impact the function of a specific neural circuit. We have developed an experimental approach to elucidate the actions of genes that cause neurodegenerative disease in a single mammalian neural circuit. Using mouse genetics, we expressed an AD gene exclusively in primary olfactory sensory neurons in a conditional manner. Characterization of this model uncovered a population of mouse olfactory neurons that undergo enhanced cell death and axon mistargeting in a non-cell autonomous fashion in the presence of this AD gene. In this proposal, we outline a series of studies to extend our analysis of this mouse model by employing: 1. longitudinal in vivo functional imaging using multiphoton microscopy and 2. primary olfactory neuron culture that can be adapted to high throughput screens for molecules that reverse the cell death phenotype. Hits from this screen can be rapidly tested in the mouse model by intranasal delivery to the olfactory epithelium. In addition, we propose to extend this experimental approach to genes associated with other neurodegenerative diseases such as PD. Elucidation of the actions of these disease genes at a systems level with novel functional and cellular outcomes from our neural circuit mouse model and characterizing additional neurodegenerative disease genes in this model system hopefully will contribute to the development of effective therapies. Public Health Relevance: Neurodegenerative diseases in general and Alzheimer's disease in particular have an enormous public health impact currently; the estimated annual cost to our society in the USA is greater than $100 billion. Moreover, the incidence is projected to quadruple in the next 30 years as the baby boomer generation moves into their seventh, eighth and ninth decades. The development of effective therapies and/or preventive measures for these diseases would alleviate the loss of the quality of life for individuals who suffer these tragic disorders and unburden our society of their economic impact. This project will hopefully contribute to our understanding of these diseases and to the development of efficacious therapeutic interventions.