Dissecting neuropeptide secretion via genome sequencing of Tetrahymena mutants

描述（由申请人提供）：神经元需要从其靶神经元释放称为神经营养因子的关键信号分子以维持生存和正常功能。这一通路的中断被认为是阿尔茨海默氏症、抑郁症和双相情感障碍等疾病的危险因素。虽然神经营养因子的调节分泌对神经元的发育和维持至关重要，但我们并不完全了解递送神经营养因子所需的分泌颗粒是如何产生或递送到需要它们的地方的。更好地理解这一过程将阐明神经元的正常功能，并可能揭示这些途径如何导致阿尔茨海默氏症和情感障碍的重要见解。我们知道，分泌颗粒生成的关键步骤，如神经营养素储存所需的步骤，是古老的进化起源，因此我们可以使用强大的遗传工具和分析方法，在单细胞生物四膜虫中识别和分析这些步骤。然后，我们可以使用在四膜虫中获得的信息来定义参与神经营养素储存的重要哺乳动物同源物。我们的方法将是利用四膜虫的特定功能，结合下一代全基因组测序，以确定一组分泌颗粒形成缺陷突变体的遗传病变。

DESCRIPTION (provided by applicant): Neurons require release of critical signaling molecules known as neurotrophins from their target neurons for survival and normal function. Disruptions in this pathway are thought to be a risk factor in diseases like Alzheimer's, depression, and bipolar disease. Although the regulated secretion of neurotrophins is critical to the development and maintenance of neurons, we do not fully understand how the secretory granules needed to deliver neurotrophins are generated or delivered to where they are needed. A better understanding of this process will illuminate the normal functioning of the neuron and may reveal important insights in how these pathways contribute to Alzheimer's and affective disorders. We know that critical steps involved in the generation secretory granules like those needed for neurotrophin storage are of ancient evolutionary origin, so we can use the powerful genetic tools and methods of analysis to identify and analyze these steps in a single- celled organism, Tetrahymena. We can then use the information gained in Tetrahymena to define essential mammalian homologues involved in neurotrophin storage. Our approach will be to exploit specific features of Tetrahymena in combination with next-generation whole genome sequencing, to identify the genetic lesions that underlie a set of mutants with defects in secretory granule formation.