The cellular basis of FMRP function

FMRP 功能的细胞基础

• 批准号: G0700967/1
• 负责人: Peter Kind
• 金额: $ 81万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2008
• 资助国家: 英国
• 起止时间: 2008 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0700967%2F1
• 关键词: cellular; basis; FMRP; function

Fragile X syndrome is the most common form of mental retardation that can be inherited from ones? parents. It is caused by the absence of a single protein called the fragile X mental retardation protein or FMRP. As the same implies, the gene that makes FMRP is located on the X chromosome. Men have one copy of the X chromosome whereas women have two copies, each containing a copy of the FMRP gene. Interestingly, the two X-chromosomes in females do not express their genes equally; during early foetal development each cell makes a decision to inactivate one X-chromosome (in a process known as X-inactivation) apparently at random. In the case of females with FXS, if a cell inactivates the chromosome containing the normal gene, the cell will not make FMRP. Similarly, if the cell inactivates the X-chromosome containing the mutant FMR1 gene, the cell will make normal levels of FMRP. Because X-inactivation is random, the severity of neurological defects in females varies depending on the relative number of mutant and normal cells. In mice, we can exploit the fact that females have normal and abnormal cells to learn about how FMRP regulates brain development and whether or not the disease is treatable to certain types of drug treatments. For example the presence of cells with normal levels of FMRP may secrete some factors that rescue the cells that do not express FMRP. Women would only show symptoms if the proportion of normal cells is too low to effectively rescue the mutant cells. In this case identification of the factors by which rescue occurs would provide excellent prospective drug therapies for male and female FXS sufferers. Alternatively, the presence of normal cells may not be able to rescue the mutant cells because the mutant cells do not have the ability to respond to factors made by the normal cells. In this case, alternative forms of treatments that either directly alter the genetics of the mutant cells or that can bypass the normal role of FMRP would have to be pursued. All of the experiments will focus on neurons of the cerebral cortex and hippocampus, brain regions that mediate cognition and memory in mammals. These experiments will therefore guide future research into treatments of FXS. Furthermore, they will be the first experiments to directly examine the development of FXS in females.

脆性X综合征是最常见的精神发育迟滞形式，可以从一个人身上遗传？父母。这是由于缺乏一种名为脆性X智力低下蛋白或FMRP的蛋白质引起的。同样，产生FMRP的基因位于X染色体上。男性有一份X染色体，而女性有两份，每一份都包含一份FMRP基因。有趣的是，女性的两条X染色体并不等同地表达它们的基因；在胎儿发育的早期，每个细胞显然是随机地决定使一条X染色体失活(这一过程被称为X染色体失活)。对于患有FXS的女性来说，如果一个细胞使包含正常基因的染色体失活，该细胞将不会产生FMRP。同样，如果细胞使含有突变的FMR1基因的X染色体失活，细胞将产生正常水平的FMRP。因为X失活是随机的，女性神经缺陷的严重程度取决于突变细胞和正常细胞的相对数量。在老鼠身上，我们可以利用女性有正常和异常细胞的事实来了解FMRP是如何调节大脑发育的，以及这种疾病是否可以通过某些类型的药物治疗来治疗。例如，FMRP水平正常的细胞的存在可能会分泌一些因子来拯救不表达FMRP的细胞。只有当正常细胞比例太低，无法有效挽救突变细胞时，女性才会出现症状。在这种情况下，确定发生抢救的因素将为男性和女性FXS患者提供极好的前瞻性药物治疗。或者，正常细胞的存在可能无法挽救突变细胞，因为突变细胞没有能力对正常细胞制造的因子做出反应。在这种情况下，必须寻求替代形式的治疗，要么直接改变突变细胞的遗传学，要么绕过FMRP的正常作用。所有的实验都将集中在大脑皮层和海马区的神经元上，这两个脑区是哺乳动物认知和记忆的中介。因此，这些实验将指导未来对FXS治疗的研究。此外，这将是第一次直接研究女性FXS发育的实验。