Phagocytosis is misregulated in a Drosophila model of Fragile X syndrome

描述（由申请人提供）： 在人类中，FMR 1功能的丧失会导致脆性X综合征，这是自闭症和智力残疾最常见的单基因原因。自闭症和脆性X综合征都与免疫系统功能改变有关。长期以来，人们一直假设大脑中失调的免疫细胞在自闭症和其他神经系统疾病的病因或进展中发挥作用。然而，驱动这些症状的分子机制知之甚少。 我们的实验室使用已建立的果蝇模型来研究脆性X综合征。FMR 1基因在果蝇和脊椎动物之间在分子水平和功能水平上都是高度保守的。与脆性X综合征患者相似，缺乏果蝇同源物dFMR 1的突变果蝇表现出神经系统症状，包括神经元结构的变化、学习和记忆缺陷、昼夜节律丧失或约24小时周期的生理振荡。dFMR 1突变体的免疫系统功能以前没有被表征。 我的初步数据表明，dFMR 1的缺失改变了两种免疫细胞的吞噬活性：免疫血细胞或巨噬细胞;和大脑中的免疫细胞或神经胶质。我推测这些吞噬作用的变化是由昼夜节律调节的丧失引起的。dFMR 1突变体，类似于许多人类自闭症患者，已经失去了他们的昼夜节律调节。我在以前的出版物中指出，巨噬细胞的吞噬作用是昼夜节律调节的。在我的初步数据中，我表明dFMR 1突变体已经失去了巨噬细胞吞噬作用的昼夜节律调节。 研究dFMR 1缺失情况下昼夜节律功能障碍和免疫的作用的该提案的具体目的是：（1）确定昼夜节律调节神经元中dFMR 1功能的丧失是否是巨噬细胞吞噬作用改变的原因;和（2）定量确定dFMR 1在神经元发育期间调节胶质细胞吞噬作用中的作用。为了支持减轻精神疾病负担的使命，我们预计，我们的研究将引入一个新的模型，在脆性X综合征的智力残疾和自闭症的原因与未来可能的影响，对疾病的治疗方法。

DESCRIPTION (provided by applicant): In humans, loss of function of FMR1 causes Fragile X syndrome, the most common monogenic cause of autism and intellectual disability. Both autism and Fragile X syndrome are associated with altered immune system function. It has long been hypothesized that misregulated immune cells in the brain play a role either in the etiology or progression of autism and other neurological diseases. However, the molecular mechanisms driving these symptoms are poorly understood. Our lab uses an established Drosophila model to study Fragile X syndrome. The FMR1 gene is highly conserved between flies and vertebrates, both on the molecular and functional levels. Similar to patients with Fragile X Syndrome, mutant flies lacking the Drosophila homolog dFMR1 exhibit neurological symptoms, including changes in neuronal structure, learning and memory defects, and loss of circadian rhythms, or physiological oscillations with a ~24hr period. The immune system function of dFMR1 mutants has not previously been characterized. My preliminary data suggest that loss of dFMR1 alters phagocytic activity by two types of immune cells: immune blood cells, or macrophages; and immune cells in the brain, or glia. I hypothesize that these change in phagocytosis are caused by loss of circadian regulation. dFMR1 mutants, similar to many human patients with autism, have lost their circadian regulation. I showed in a previous publication that phagocytosis by macrophages is circadian-regulated. In my preliminary data, I show that dFMR1 mutants have lost circadian regulation of phagocytosis by macrophages. The Specific Aims of this proposal to investigate the roles of circadian dysfunction and immunity in the absence of dFMR1 will be: (1) to determine whether the loss of dFMR1 function in circadian regulatory neurons is responsible for altered phagocytosis by macrophages; and (2) to quantitatively determine the role of dFMR1 in regulating phagocytosis by glia during neuronal development. In support of the mission of reducing the burden of mental illness, we anticipate that our research will introduce a new model of the cause of intellectual disability and autism in Fragile X syndrome with possible future implications for therapeutic approaches to the disease.