The Control of Neuronal Diversity and Plasticity by the let-7-C microRNA Pathway

描述(申请人提供)：本申请概述了一项基础研究计划，该计划利用果蝇模式生物来阐明控制神经可塑性的基本分子机制。神经可塑性是神经系统的一般特征，它解释了成年人的大脑如何随着时间的推移以及对包括激素、营养、日光和经验在内的不同外部刺激的反应而发生变化。神经可塑性缺陷与多种精神障碍有关，包括抑郁症、双相情感障碍和精神分裂症。了解控制神经可塑性的分子机制将导致旨在治疗和治愈这些和其他精神疾病的治疗干预措施。这一应用的中心假设是let-7-Complex microRNA(MiRNA)途径是成年期和发育过程中神经可塑性的主要调节因子。MiRNAs是新近发现的一类调控靶基因表达的调控RNA，let-7-复合体编码三个高度保守且共转录的神经miRNAs，miR-100、let-7和miR-125。虽然许多miRNAs在成人的大脑中表达，但目前还没有已知的例子表明，在活体中的大脑功能所需的miRNAs。根据我们新的初步数据，我认为let-7-Complex miRNA途径至少调控神经可塑性的三个方面：突触可塑性、神经干细胞可塑性和轴突重塑。此外，我认为let-7-复合体miRNA途径以相同的方式调节这些过程中的每一个，通过转录后调节一小群调节神经元形态的剂量敏感转录因子的表达。为了验证这一模型，我将全面表征果蝇中let-7-Complex miRNA途径的分子、细胞和行为功能，具体如下：1)确定let-7-Complex miRNAs在果蝇蘑菇体中的发育和发育后功能；2)联系let-7-Complex miRNAs的分子、细胞和行为需求；3)确定调控let-7-Complex miRNAs表达或活性的因素是否也调节神经可塑性。通过阐明在神经元生命的多个阶段控制可塑性的高度保守的机制，该项目将使调节神经可塑性的分子疗法的设计成为可能，从而治疗多种精神障碍。精神疾病，如压力、抑郁、自闭症、躁郁症和精神分裂症，都与神经可塑性缺陷有关。在这项拨款申请中，我描述了旨在确定控制果蝇神经可塑性的潜在机制的实验，果蝇是一种遗传上易驯化的模式生物。这一机制是由let-7-复杂的microRNAs对特定的剂量敏感的转录因子进行转录后调控。鉴于let-7-复杂的microRNAs、它们的靶标及其神经表达谱从苍蝇到人类的保守，我预计这项工作将阐明控制人类神经可塑性的多个方面的基本表观遗传途径，从而广泛影响精神疾病的治疗。

DESCRIPTION (provided by applicant): This application outlines a basic research plan that utilizes the fruit fly model organism to illuminate a fundamental molecular mechanism controlling neuroplasticity. Neuroplasticity is a general feature of the nervous system and explains how the adult brain changes over time and in response to heterogeneous external stimuli, including hormones, nutrition, daylight and experience. Defects in neuroplasticity have been associated with multiple mental disorders, including depression, bipolar disorder, and schizophrenia. Understanding the molecular mechanisms controlling neuroplasticity will lead to therapeutic interventions designed to treat and cure these and other mental illnesses. The central hypothesis of this application is that the let- 7-Complex microRNA (miRNA) pathway is a major regulator of neuroplasticity during adulthood as well as development. MiRNAs are a recently discovered class of regulatory RNAs that control the expression of target genes and the let-7-Complex encodes three highly conserved and co-transcribed neural miRNAs, miR-100, let-7 and miR-125. Although many miRNAs are expressed in the adult human brain, there are currently no known examples of miRNAs that are required for brain function in vivo. Based on our novel preliminary data, I propose that the let-7- Complex miRNA pathway regulates at least three aspects of neuroplasticity: synaptic plasticity, neural stem cell plasticity, and axodendritic remodeling. Furthermore, I propose that the let-7- Complex miRNA pathway regulates each of these processes in the same way, by post- transcriptionally modulating the expression of a small group of dosage-sensitive transcription factors that regulate neuronal morphology. To test this model, I will comprehensively characterize the molecular, cellular and behavioral function of let-7-Complex miRNA pathway in the fruit fly, as follows: 1) determine the developmental and post-developmental function of let- 7-Complex miRNAs in the fly mushroom body, 2) relate the molecular, cellular and behavioral requirements of let-7-Complex miRNAs, and 3) identify whether factors that regulate the expression or activity of let-7-Complex miRNAs also modulate neuroplasticity. By illuminating a highly conserved mechanism that controls plasticity during multiple phases of a neuron's life, this project will enable the design of molecular therapies that adjust neuroplasticity and thereby treat multiple mental disorders. Mental illnesses like stress, depression, autism, bipolar disorder and schizophrenia have all been associated with defects in neuroplasticity. In this grant application, I describe experiments designed to identify an underlying mechanism controlling neuroplasticity in the fruit fly, which is a genetically tractable model organism. This mechanism is the post-transcriptional regulation of specific dosage-sensitive transcription factors by let-7-Complex microRNAs. Given the conservation of the let-7-Complex microRNAs, their targets, and their neural expression profiles from flies to humans, I anticipate that this work will illuminate a fundamental epigenetic pathway controlling multiple aspects of neuroplasticity in humans and thereby broadly impact the treatment of mental illness.