Investigation of sex differences associated with autism candidate gene, Cyfip1

自闭症候选基因Cyfip1相关性别差异的调查

基本信息

批准号：
8058160
负责人：
Donna Marie Werling
金额：
$ 3.16万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8058160
关键词：
Accounting Actins Adult Affect Anatomy Animals Autistic Disorder Automobile Driving Awareness Axon Behavior Binding Biological Brain Brain region Candidate Disease Gene Cells Cerebellum Child Cognition Complex Cytoskeleton Data Dendrites Development Disease Engineering Etiology FMR1 Family Female Fragile X Mental Retardation Protein Fragile X Syndrome Functional disorder Genes Genetic Genetic Translation Golgi Apparatus Gonadal Steroid Hormones Growth Hippocampus (Brain)Hormones Human Individual Investigation Knock-out Knockout Mice Knowledge Lead Link Measures Mediating Messenger RNA Mind Molecular Molecular Genetics Mus Nature Neonatal Nervous system structure Neurons Pathologic Pathology Pathway interactions Pattern Pharmacologic Substance Phenotype Population Prevalence Preventive Process Proteins Public Health Regulation Role Schools Severities Sex Characteristics Sex Ratio Signal Transduction Staging Staining method Stains Structure Supplementation Support System Techniques Testing Testosterone Time Transcript Transgenic Mice Transgenic Organisms Western Blotting X Chromosome autism spectrum disorder base brain morphology dosage frontal lobe human TFRC protein insight link protein male mature animal migration mouse model neurobiological mechanism neurodevelopment neurogenesis neuronal cell body postnatal protein complex public health relevance relating to nervous system research study sex sexual dimorphism synaptogenesis

项目摘要

DESCRIPTION (provided by applicant): Autism spectrum disorders (ASDs) are a group of pervasive neurodevelopment conditions that currently affect 1 in 150 individuals, making ASDs a notable public health issue. Although the cause of ASDs is unknown in the majority of cases, it is known that ASDs affect at least four times as many males as females, and that ASDs are highly heritable, indicating a strong genetic contribution. Continued identification of genes associated with ASDs has advanced our understanding of the role of genetics in ASDs, but the skewed sex ratio in prevalence remains unexplained. To this end, studying a candidate gene that shows sex differences in expression patterns or associated neural phenotypes may provide unique insights into ASD pathophysiology. Data from the Geschwind lab show that cytoplasmic FMRP-interacting protein 1 (CYFIP1) expression patterns are sexually dimorphic, and that neuropathological phenotypes associated with Cyfip1 over-expression may also show sexual dimorphisms, making this candidate gene a unique target for study. CYFIP1 has also been implicated in neural development and function by its interactions with FMRP, the protein silenced in Fragile X Syndrome, and by its involvement in Rac1 signaling and the WAVE complex for regulation of actin remodeling, a process crucial for axon elongation and dendritic development. To further study the function of CYFIP1 in the mammalian nervous system, our lab has engineered a transgenic mouse model that over-expresses Cyfip1. The purpose of the proposed project is to utilize this mouse model to better understand the implications of the sexual dimorphism in Cyfip1 expression in neural development and ASD pathophysiology. Aim 1 will determine when (at which developmental time points) and where (in which brain regions) sex differences in Cyfip1 expression occur, using quantitative real time PCR and western blotting to assess transcript and protein levels. Aim 2 will determine which neuronal phenotypes associated with Cyfip1 over-expression are sexually dimorphic by using immunohistochemical and Golgi cell staining techniques to visualize the structure and organization of specific populations of neurons. Aim 3 will utilize sex steroid hormone manipulation techniques to investigate potential mechanisms driving the sexually dimorphic neuronal phenotypes identified in Aim 2. Together, results from these aims will further our understanding of how perturbations in expression of an autosomal ASD candidate gene can elicit differing effects on neural development in males and females. Continued investigation along these lines will accelerate identification of those factors that cause males to be vulnerable to, or females to be protected from, ASDs, thereby facilitating the development of pharmaceutical treatments and preventive measures for ASDs. PUBLIC HEALTH RELEVANCE: Autism spectrum disorders (ASDs) are neurodevelopment conditions that place significant burden on the families, schools, and support systems of affected children, and although public awareness has increased, the cause of these disorders remains unknown in the vast majority of cases. However, a few features of ASDs are well known: ASDs are highly heritable, indicating a strong genetic contribution to their development, and ASDs affect at least four times as many males as females. Therefore, the study of sex differences associated with an autism candidate gene, CYFIP1, aims to open doors for understanding more about the biological basis for the sex difference in the prevalence of ASDs, while advancing current knowledge about potential causative mechanisms and neurobiological features of ASDs.

描述（由申请人提供）：自闭症谱系障碍 (ASD) 是一组普遍存在的神经发育疾病，目前影响每 150 人中就有 1 人，使 ASD 成为一个值得注意的公共卫生问题。尽管在大多数情况下，自闭症谱系障碍的病因尚不清楚，但众所周知，自闭症谱系障碍影响的男性数量至少是女性的四倍，而且自闭症谱系障碍具有高度遗传性，表明遗传因素具有很强的影响。与自闭症谱系障碍相关基因的不断鉴定加深了我们对遗传学在自闭症谱系障碍中的作用的理解，但患病率的性别比例失调仍然无法解释。为此，研究在表达模式或相关神经表型方面表现出性别差异的候选基因可能会为 ASD 病理生理学提供独特的见解。 Geschwind 实验室的数据显示，细胞质 FMRP 相互作用蛋白 1 (CYFIP1) 表达模式具有性别二态性，与 Cyfip1 过度表达相关的神经病理表型也可能表现出性别二态性，使该候选基因成为独特的研究目标。 CYFIP1 还通过与 FMRP（脆性 X 综合征中沉默的蛋白质）相互作用，以及参与 Rac1 信号传导和调节肌动蛋白重塑的 WAVE 复合体（对于轴突伸长和树突发育至关重要的过程），与神经发育和功能有关。。为了进一步研究CYFIP1在哺乳动物神经系统中的功能，我们实验室构建了过度表达Cyfip1的转基因小鼠模型。该项目的目的是利用该小鼠模型更好地了解 Cyfip1 表达的性别二态性在神经发育和 ASD 病理生理学中的影响。目标 1 将使用定量实时 PCR 和蛋白质印迹法评估转录物和蛋白质水平，确定 Cyfip1 表达的性别差异何时（在哪个发育时间点）和何处（在哪个大脑区域）发生。目标 2 将使用免疫组织化学和高尔基细胞染色技术来可视化特定神经元群体的结构和组织，从而确定哪些与 Cyfip1 过度表达相关的神经元表型具有性别二态性。目标 3 将利用性类固醇激素操纵技术来研究驱动目标 2 中确定的性二态性神经元表型的潜在机制。总之，这些目标的结果将进一步加深我们对常染色体 ASD 候选基因表达的扰动如何引起不同影响的理解。男性和女性的神经发育。沿着这些思路继续进行调查将加速识别导致男性易患自闭症谱系障碍或女性免受自闭症谱系障碍的因素，从而促进针对自闭症谱系障碍的药物治疗和预防措施的开发。公共卫生相关性：自闭症谱系障碍 (ASD) 是一种神经发育疾病，给受影响儿童的家庭、学校和支持系统带来沉重负担，尽管公众意识有所提高，但在绝大多数情况下，这些疾病的原因仍然未知。然而，自闭症谱系障碍的一些特征是众所周知的：自闭症谱系障碍具有高度遗传性，这表明遗传对其发育有很强的贡献，并且自闭症谱系障碍影响的男性数量至少是女性的四倍。因此，对与自闭症候选基因 CYFIP1 相关的性别差异的研究，旨在为更多地了解自闭症患病率性别差异的生物学基础打开大门，同时推进目前对自闭症潜在致病机制和神经生物学特征的认识。