Role of Fragile X Mental Retardation Protein on Gene Expression in Auditory Brainstem Development

脆性X智力低下蛋白对听觉脑干发育中基因表达的作用

• 批准号: 10934302
• 负责人: HITOMI SAKANO
• 金额: $ 12.46万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10934302
• 关键词: Role; Fragile; Mental; Retardation; Protein

Fragile X Syndrome (FXS) is the most common heritable autism spectrum disorder and is associated with auditory features such as hypersensitivity to sound (hyperacusis). FXS is caused by the absence of Fragile X mental retardation protein (FMRP), which is known to bind specific mRNAs and repress their translation. Little is known about how FMRP impacts the central auditory pathway. We will study FMRP effects on gene expression in the auditory brainstem, using the well-established fmr1-knockout (KO) mouse model, which exhibits auditory hypersensitivity and seizures in response to loud noise. Although the well-established role of FMRP is translational repression, it has been shown recently in neurons that FMRP can also change the level of many mRNAs. Whether this occurs in the auditory brainstem is unknown. We have novel transcriptome data (unpublished) showing that the levels of many mRNAs that are known to be bound by FMRP, and to function in synaptic pathways, are decreased in the fmr1-KO cochlear nucleus. How this occurs is not known. Aim 1 will test the hypothesis that direct FMRP binding stabilizes the bound mRNA, but in the absence of FMRP, these mRNAs have decreased stability (and, therefore, decreased level). We will also determine if decreased stabilization of mRNA leads to decreased protein level or if it is offset by the loss of FMRP-mediated translational repression so as to manifest as increased protein level. Another possibility is that FMRP acts indirectly through translational repression of factors, such nonsense-mediated mRNA decay (NMD) factor, UPF1. Unpublished data from my research mentor’s lab has shown that induced pluripotent stem cells derived from FXS-patient fibroblasts manifest an abnormally high level of UPF1 (whose mRNA is bound by FMRP), resulting in hyperactivated NMD and, as a consequence, reduced levels of cellular NMD target mRNAs. Based on these data, Aim 2 will test the hypothesis that NMD is hyperactivated in fmr1-KO cochlear nucleus, leading to gene downregulation. Lastly, it is known that FMRP is involved in activity dependent processes. For example, dendritic localization of FMRP is increased with glutamatergic signaling and loss of afferent activity can blunt translational repression by FMRP. Aim 3 will test the hypothesis that the FMRP effects on gene expression are dependent on afferent activity. We will examine an inducible deafness mouse model to determine if it can phenocopy the fmr1-KO, indicating that afferent activity is required for FMRP function. The PI has extensive molecular biology experience, and with the guidance of a primary mentor who is a respected RNA biologist. The PI will master current RNA techniques and work towards becoming an independent investigator. Results will reveal how FMRP regulates genes important for auditory development and plasticity. The ultimate goal is to reveal potential therapeutic targets to treat auditory hypersensitivity and processing disorders. The mechanism leading to hyperacusis is poorly understood, and because it is not limited to FXS and affects up to 15% of the population, the study is relevant to the general population.

脆性X染色体综合征（FXS）是最常见的遗传性自闭症谱系障碍，与