Foxp2 regulation of sex specific transcriptional pathways and brain development

Foxp2对性别特异性转录途径和大脑发育的调节

基本信息

批准号：
9203690
负责人：
jerald michael bowers
金额：
$ 24.9万
依托单位：
VIRGINIA POLYTECHNIC INST AND ST UNIV
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9203690
关键词：
Address Adolescent Adult Affect Amino Acids Androgens Animal Model Animals Anorexia Anxiety Disorders Area Autistic Disorder Behavior Behavioral Biological Biological Models Brain Brain region Bulimia Candidate Disease Gene Cell Line Centers for Disease Control and Prevention (U.S.)Cerebellum ChIP-seq Child Childhood Communication Corpus striatum structure DNA Sequence Data Development Disease Dyslexia Employee Strikes Etiology Exhibits Exposure to FOXP2 gene Family Female Functional disorder Gender Gene Expression Regulation Genes Genetic Gilles de la Tourette syndrome Goals Gonadal Steroid Hormones Health Human Impairment Incidence Individual Knowledge Laboratory mice Language Major Depressive Disorder Mediating Mental disorders Methodology Methods Modeling Molecular Morphology Neocortex Neonatal Neurites Neuronal Differentiation Neurons Phase Play Prevalence Preventive Preventive treatment Primates Production Proteins Rattus Regulation Relative Risks Reporting Research Risk Role Schizophrenia Sex Bias Sex Characteristics Sexual Development Signal Pathway Social Behavior Social Environment Social Interaction Source Study models Stuttering Subfamily lentivirinae Symptoms Testing Therapeutic Ultrasonics Work Writing autism spectrum disorder base brain pathway cognitive function design disorder prevention early onset gender difference insight interest knock-down male member nervous system disorder neural circuit neuron development prenatal pup research study sex social theories transcription factor transcriptome sequencing vocalization

项目摘要

DESCRIPTION (provided by applicant): The relative risk of developing a mental illness or neurological disorder varies considerably by gender. Males exhibit far higher rates of autism and autism spectrum disorder (ASD), Tourette's Syndrome, stuttering, dyslexia, and early onset of schizophrenia, all of which have a childhood onset. In contrast, females suffer much higher incidences of major depressive disorders, general anxiety disorder, anorexia, bulimia, and late onset of schizophrenia, all of which have adult onsets. The biological basis for these gender biases is entirely unknown. By exploring how the brain develops differently in males and females, using a mammalian animal model, we can gain insight into the potential sources of the sex differences in disease and identify potential therapeutic and preventive targets. Moreover, the gene FOXP2 is known to be expressed in several areas of the brain involved in vocal communication in animals and language in humans. There is strong support for FOXP2 playing a role in ASD can be found in its regulation of downstream signaling pathways. The mechanism that explains the basis for the gender difference in human language is also unknown, although, sex hormones, principally androgens, are known to play a central role in the development of vocalizations in a wide variety of animal species including primates. It has also been hypothesized that exposure to increased levels of androgens, during prenatal development, underpin the etiology of ASD, although to date, no relationship between any autism associated gene, language, or sex hormones has been established. The first goal of this proposal is to investigate how sex differences in Foxp2 expression influence the development of sex specific neural circuitry and how this circuitry is accountable for sex specific behaviors (e.g., vocal communication and social interactions). Experiments 1.1 and 1.2 are designed to fill the first gap in our knowledge, by exploring how suppression of Foxp2 during the neonatal developmental period impacts both vocalization and social behavior differently in males versus females. As discussed above, previous work investigating ASD and FOXP2, has not taken the perspective of the potential impact sex differences and hormones have on transcriptional signaling pathways regulated by FOXP2. Thus, A second goal of this proposal is to determine how sex hormones mediate Foxp2's regulation of gene expression. Experiments 2.1 and 2.2 are designed to address this question by assessing what are the effects sex hormones have on Foxp2 transcriptional signaling pathways. From previous research, it is known that Foxp2 influences the development of brain regions responsible for higher cognitive functioning. However, to date it is not known to what extent this development is similar or different with regards to male and female brain development. The third goal of this proposal is to ascertain the extent to which the interaction of sex hormones and Foxp2 alters sex specific neuronal development. Experiments 3.1 and 3.2 are designed to address this question by quantifying the impact sex hormones have on Foxp2 protein levels both in the presence and absence of lentiviral knockdown targeting Foxp2. For the R00 phase, I will write up the research collected from Aims 1.2 and Aims 2.1 and 2.1. I will then begin setting up my lab. Concurrent with opening the lab, I will begin work on Aim 3.

描述（由申请人提供）：患有精神疾病或神经系统疾病的相对风险因性别而异。雄性表现出更高的自闭症和自闭症谱系障碍（ASD），图雷特综合征，口吃，阅读障碍和精神分裂症早期发作的率，所有这些都有童年的发作。相比之下，女性的主要抑郁症，普通焦虑症，厌食症，贪食症和精神分裂症晚期发作的发生率更高，所有这些都有成人的进攻。这些性别偏见的生物学基础是完全未知的。通过使用哺乳动物模型探索大脑在男性和女性中的发展方式，我们可以深入了解疾病中性别差异的潜在来源，并确定潜在的治疗和预防靶标。此外，已知基因FOXP2在人类的动物和语言中涉及大脑的几个领域表达。在其下游信号通路的调节中，可以找到对FOXP2在ASD中发挥作用的强烈支持。解释人类语言性别差异的基础的机制也未知，尽管众所周知，性激素（主要是雄激素）在包括灵长类动物在内的各种动物物种中发声中起着核心作用。还可以假设，在产前发育期间，在ASD的病因中受到雄激素水平的增加，尽管迄今为止，尚未建立任何自闭症相关的基因，语言或性激素之间的关系。该提案的第一个目标是研究FOXP2表达中的性别差异如何影响性别特定神经回路的发展，以及该电路如何对性别特定行为负责（例如，声带交流和社交互动）。实验1.1和1.2旨在通过探索在新生儿发育期间对FOXP2的抑制如何影响男性与女性的声音和社会行为的影响，以填补我们所知的第一个空白。如上所述，先前研究ASD和FOXP2的工作并未对性别差异和激素对FOXP2调节的转录信号通路的潜在影响。因此，该提案的第二个目标是确定性激素如何介导FOXP2的基因表达调节。实验2.1和2.2旨在通过评估性激素对FOXP2转录信号通路的影响是什么，以解决这个问题。从先前的研究中，众所周知，FOXP2会影响负责更高认知功能的大脑区域的发展。但是，迄今为止，对于男性和女性脑发育，这种发展在多大程度上是相似或不同的。该提案的第三个目标是确定性激素和FOXP2的相互作用在多大程度上改变性别特定的神经元发展。实验3.1和3.2旨在通过量化性激素对FOXP2的影响和不存在针对FOXP2的影响，以解决性激素对FOXP2蛋白水平的影响。对于R00阶段，我将写出AIMS 1.2和AIMS 2.1和2.1收集的研究。然后，我将开始设置我的实验室。与开放实验室的同时，我将开始在AIM上工作 3。