Dissecting neuropeptide secretion via genome sequencing of Tetrahymena mutants

描述(申请人提供)：神经元需要从它们的目标神经元释放被称为神经营养因子的关键信号分子来生存和正常功能。这一通路的中断被认为是阿尔茨海默氏症、抑郁症和躁郁症等疾病的风险因素。尽管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运送神经营养因子所需的分泌颗粒是如何产生或输送到需要它们的地方的。对这一过程的更好理解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。我们知道，像储存神经营养素所需的分泌颗粒所涉及的关键步骤是起源于古老的进化，所以我们可以使用强大的遗传工具和分析方法来识别和分析单细胞有机体四膜虫中的这些步骤。然后，我们可以使用在四膜虫中获得的信息来定义与神经营养素储存有关的基本哺乳动物同源物。我们的方法将是利用四膜虫的特定特征，结合下一代全基因组测序，识别一组具有分泌颗粒形成缺陷的突变体背后的遗传损伤。 与公共卫生相关：阿尔茨海默病是一个巨大的、日益严重的公共卫生问题，其病因仍然知之甚少。其中一个因素似乎是神经细胞储存和释放被称为神经营养素的信号分子。通过研究单细胞生物体中类似的途径，我们可以确定存储神经营养素所需的关键基因，从而有助于理解该途径中的缺陷如何导致疾病。

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. PUBLIC HEALTH RELEVANCE: Alzheimer's disease represents an enormous and growing public health problem, whose etiology is still poorly understood. One contributing factor appears to be the storage and release from nerve cells of signaling molecules called neurotrophins. By studying a similar pathway in a single-celled organism, we can identify key genes that are required for neurotrophin storage, and thereby help to understand how defects in this pathway can lead to disease.