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Genetic control of sex differences in the nervous system

神经系统性别差异的遗传控制

基本信息

批准号：
7747963
负责人：
Douglas S Portman
金额：
$ 25万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-01-01 至 2012-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7747963
关键词：
Address Affect Afferent Neurons Animals Autistic Disorder Behavior Binding Sites Biological Caenorhabditis elegans Calcium Candidate Disease Gene Cells Characteristics Consensus Coupled Development Drosophila genus Family Gene Expression Gene Family Genes Genetic Hormones Human Light Link Mediating Mediator of activation protein Mental Health Modeling Modification Molecular Molecular Genetics Mood Disorders Nematoda Nervous System Physiology Nervous system structure Neurobiology Neurologic Neurons Neurophysiology - biologic function Pattern Predisposition Property Regulation Regulatory Pathway Research Resolution Role Sex Bias Sex Characteristics Sexual Development Shapes Smell Perception Soil Stimulus Syndrome Work cell growth regulation cell type chronic pain combinatorial design genome-wide innovation insight interest male member nervous system disorder neurodevelopment neuromechanism neuroregulation preference programs public health relevance relating to nervous system response sex synaptic function transcription factor

项目摘要

DESCRIPTION (provided by applicant): Sex differences in the nervous system and in behavior are ubiquitous in the animal kingdom. Beyond their basic biological interest, these differences have important implications for understanding the sex bias that characterizes many mental health and neurological disorders. An intriguing but poorly understood component of nervous system sex differences arises through the actions of hormone-independent, cell-intrinsic "neural sex" in shaping characteristics of the nervous system. In preliminary work using the nematode C. elegans, we have identified robust sex differences in olfactory behavior that arise through cell-intrinsic, sex-dependent modification of the function of neurons common to both sexes. Understanding the mechanisms that underlie these sex differences has great potential to shed light on similar phenomena acting in the mammalian CNS. In three Specific Aims, we will (1) identify the precise neural foci that regulate sex differences in olfaction, and characterize sex differences in the development and function of these neurons; (2) use a candidate-gene approach as well as targeted microarray studies to identify sex-regulated genes in the core nervous system and determine their functional significance; and (3) characterize the role of C. elegans members of the conserved DM family of sexual regulators, including dmd-3, in generating sex differences in olfaction. Together, this work takes an innovative approach to illuminating the conserved molecular, genetic and neural mechanisms by which neural sex is coupled to sex differences in the development and function of the nervous system. PUBLIC HEALTH RELEVANCE Using a tiny soil roundworm, we will examine the genetic and cellular regulation of sex differences in the development and function of the nervous system. These studies will identify genes and mechanisms that may have important roles in human mental health and neurological conditions, such as autism, mood disorders and chronic pain syndrome, that preferentially affect one sex over the other.

描述（由申请人提供）：在动物王国中，神经系统和行为的性别差异是普遍存在的。除了基本的生物学意义之外，这些差异对理解以许多精神健康和神经疾病为特征的性别偏见具有重要意义。神经系统性别差异的一个有趣但鲜为人知的组成部分是通过激素独立的、细胞内在的“神经性别”在塑造神经系统特征中的作用而产生的。在使用线虫秀丽隐杆线虫的初步工作中，我们已经确定了嗅觉行为的强大性别差异，这种差异是通过细胞内在的、性别依赖的、两性共有的神经元功能的修改而产生的。了解这些性别差异背后的机制，对于揭示哺乳动物中枢神经系统中的类似现象具有很大的潜力。在三个具体目标中，我们将(1)确定调节嗅觉性别差异的精确神经病灶，并表征这些神经元发育和功能的性别差异；(2)利用候选基因方法和靶向微阵列研究鉴定核心神经系统中的性别调节基因并确定其功能意义；(3)描述了秀丽隐杆线虫的保守性调节因子DM家族成员（包括dmd-3）在嗅觉性别差异产生中的作用。总之，这项工作采用了一种创新的方法来阐明保守的分子、遗传和神经机制，通过这些机制，神经性别与神经系统发育和功能中的性别差异相耦合。利用一种微小的土壤蛔虫，我们将研究神经系统发育和功能中性别差异的遗传和细胞调节。这些研究将确定可能在人类精神健康和神经疾病（如自闭症、情绪障碍和慢性疼痛综合征）中发挥重要作用的基因和机制，这些基因和机制优先影响一种性别而不是另一种性别。