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

• 批准号: 8229889
• 负责人: Donna Marie Werling
• 金额: $ 3.24万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 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/8229889
• 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; FMRP; 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; Neurophysiology - biologic function; 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

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（ASDS）是一组普遍的神经发育状况，目前影响150个人中有1个，使ASDS成为一个显着的公共健康问题。尽管在大多数病例中，ASD的原因尚不清楚，但众所周知，ASD的影响至少是女性的四倍，而ASD是高度遗传的，表明遗传贡献很大。与ASD相关的基因的持续鉴定已经提高了我们对遗传学在ASD中的作用的理解，但是偏斜的性别比仍无法解释。为此，研究显示出表达模式或相关神经表型中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。来自Geschwind实验室的数据表明，细胞质FMRP相互作用蛋白1（CYFIP1）表达模式是性二态性的，并且神经病理学表型与CYFIP1过表达相关，也可能显示出性二态性，使该候选基因成为研究的独特目标。 CYFIP1还与神经发育和功能有关，其与FMRP的相互作用，蛋白质沉默的X综合征，以及它参与RAC1信号传导和调节肌动蛋白重塑的波复合物，这对于轴突延长和树枝状发育至关重要。为了进一步研究CYFIP1在哺乳动物神经系统中的功能，我们的实验室设计了一种过表达Cyfip1的转基因小鼠模型。拟议项目的目的是利用该小鼠模型更好地了解性二态性在CYFIP1表达中在神经发育和ASD病理生理学中的含义。 AIM 1将使用定量的实时PCR和Western印迹来评估转录本和蛋白质水平，将确定何时（在哪个发育时间点）和在哪些大脑区域（在哪个大脑区域）发生性别差异。 AIM 2将通过使用免疫组织化学和高尔基细胞染色技术来可视化神经元的结构和组织，通过使用免疫组织化学和高尔基细胞染色技术来确定与CYFIP1过表达相关的哪些神经元表型具有性二态性。 AIM 3将利用性类固醇激素操纵技术来研究AIM 2中确定的性二态性神经元表型的潜在机制。共同，这些目标的结果将进一步了解我们对女性ASD候选基因表达的扰动如何促进对男性和女性神经发育的不同影响。沿着这些线路继续进行研究将加速鉴定导致雄性容易受到ASD或女性免受ASD的影响或女性的因素，从而促进了药物治疗的发展和ASD的预防措施。 公共卫生相关性：自闭症谱系障碍（ASDS）是神经发育状况，对受影响儿童的家庭，学校和支持系统造成了巨大负担，尽管公众意识增加了，但在绝大多数情况下，这些疾病的原因仍然未知。但是，ASD的一些特征是众所周知的：ASD是高度遗传的，表明对其发育的遗传贡献很强，ASD的影响至少是女性的四倍。因此，研究与自闭症候选基因CYFIP1相关的性别差异的研究旨在打开大门，以更多地了解ASDS患病率的性别差异的生物学基础，同时促进当前有关ASDS潜在病因机制和神经生物学特征的知识。