Prader-Willi综合征（PWS）是由于第15号染色体异常所导致的神经发育疾病，发病率约为1/15000。PWS患者以过度肥胖及智能障碍等为主要临床特征。同时患者多表现出睡眠结构和睡眠节律的异常，然而其具体机制还不明确。在前期工作中，我们发现PWS致病基因Necdin蛋白可以与节律核心分子Bmal1相互作用，增加Bmal1稳定性，调节昼夜节律基因表达。我们通过酵母双杂交筛选到一个Necdin的相互作用蛋白，HSP90的共分子伴侣X。因此，我们提出下列科学假设：Necdin，HSP90和X蛋白形成复合体共同调节Bmal1蛋白折叠，干扰复合体的形成将促进Bmal1的泛素化降解，导致昼夜节律基因表达和昼夜节律的异常。本项目拟在前期工作的基础上，进一步在细胞和动物水平阐明Necdin调节Bmal1稳定性及昼夜节律的分子机制。本项目的完成将可促进PWS的诊治，有助于发现睡眠节律调控的新机制。

Prader-Willi syndrome (PWS) is a neurodevelopmental disease caused by abnormalities in the 15q11-q13 region of chromosome 15 with a prevalence of 1/15000. Individuals with this disorder is characterized by a range of psychological and physiological abnormalities including hyperphagia, extreme obesity and intellectual disability. PWS patients usually accompany with autism phenotypes and abnormalities in sleep architecture and circadian rhythm of sleep. However, the mechanisms underlying abnormal circadian rhythm in PWS patients are still elusive. In previous studies, we found that Necdin, a maternally imprinted gene mapping to PWS region, is highly expressed in the suprachiasmatic nucleus (SCN), the pacemaker of mammalian circadian clocks. We also found that Necdin interacted with and stabilized Bmal1. Further, by using yeast two-hybrid screening, we identified a co-chaperone of HSP90 interacted with Necdin. Therefore, we proposed that Necdin, HSP90 and this co-chaperone formed a complex to regulate the refolding of Bmal1. Interference of this complex promoted the degradation of Bmal1 protein through the ubiquitin proteasome pathway, leading to altered circadian rhythms and clock genes expression. In this project, we propose to elucidate the mechanisms underlying the regulation of Necdin on Bmal1 stability and circadian rhythms at the levels of cell biology and model organism. The accomplish of this project will not only improve the diagnosis and treatment of PWS, but also identify novel regulatory pathways for circadian rhythms.