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

• 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
• 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

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）：患精神疾病或神经系统疾病的相对风险因性别而异。男性患自闭症和自闭症谱系障碍 (ASD)、抽动秽语综合征、口吃、阅读障碍和早发精神分裂症的比例要高得多，所有这些疾病都在儿童期发病。相比之下，女性患重度抑郁症、广泛性焦虑症、厌食症、暴食症和迟发性精神分裂症的发病率要高得多，所有这些疾病都会在成年后发病。这些性别偏见的生物学基础完全未知。通过使用哺乳动物模型探索男性和女性大脑的不同发育方式，我们可以深入了解疾病性别差异的潜在来源，并确定潜在的治疗和预防目标。此外，已知 FOXP2 基因在涉及动物声音交流和人类语言的大脑多个区域中表达。 FOXP2 在 ASD 中发挥作用的有力证据可以在其对下游信号通路的调节中找到。尽管已知性激素（主要是雄激素）在包括灵长类动物在内的多种动物发声发育中发挥着核心作用，但解释人类语言性别差异的基础机制尚不清楚。还有假设认为，在产前发育过程中暴露于升高水平的雄激素是自闭症谱系障碍的病因学的基础，尽管迄今为止，尚未确定任何自闭症相关基因、语言或性激素之间的关系。该提案的第一个目标是研究 Foxp2 表达的性别差异如何影响性别特异性神经回路的发育，以及该回路如何负责性别特异性行为（例如声音交流和社交互动）。实验 1.1 和 1.2 旨在通过探索新生儿发育期间 Foxp2 的抑制如何对男性和女性的发声和社会行为产生不同的影响，来填补我们知识中的第一个空白。如上所述，之前研究 ASD 和 FOXP2 的工作并未考虑性别差异和激素对 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 对基因表达的调节。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来解决这个问题。从之前的研究来看，Foxp2 影响负责高级认知功能的大脑区域的发育。然而，迄今为止，尚不清楚男性和女性大脑发育的这种发育在多大程度上相似或不同。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异性神经元发育。实验 3.1 和 3.2 旨在通过量化在存在和不存在针对 Foxp2 的慢病毒敲低的情况下性激素对 Foxp2 蛋白水平的影响来解决这个问题。对于 R00 阶段，我将撰写从目标 1.2 以及目标 2.1 和 2.1 收集的研究成果。然后我将开始建立我的实验室。在开放实验室的同时，我将开始 Aim 的工作 3.