Sterol metabolism in Rett syndrome

 描述（由申请人提供） Rett综合征（RTT）是一种主要影响女性的衰弱性神经发育障碍。虽然很明显，在一个单一的基因（MECP 2）突变导致的疾病，病理背后的确切机制还没有得到很好的理解。RTT患者的自然史研究以及使用RTT小鼠模型和RTT患者iPSC模型的研究都有助于我们目前对该疾病的理解。由于每个实验平台都有其独特的优势和局限性，在特定平台上获得的见解对治疗开发有用之前，在多个平台上跨学科验证研究结果至关重要。最近，RTT小鼠模型中的抑制剂筛选已经确定胆固醇代谢的改变可能影响疾病进展，为潜在的干预打开了大门，因为该途径中的许多关键参与者是其他不相关疾病的药物靶点。然而，小鼠研究没有确定大脑中胆固醇代谢改变的细胞来源。随后的两项研究进一步证明了RTT患者血浆和成纤维细胞中胆固醇代谢的一些损伤。然而，这些研究的意义是有限的，因为血浆胆固醇水平与脑胆固醇稳态不相关，并且成纤维细胞是众所周知的脑细胞模型，因此未回答异常胆固醇代谢对Rett综合征发病机制的潜在贡献的问题，Rett综合征是一种广泛认可的神经生物学病症。这两项研究还未回答的问题是观察到的胆固醇异常与RTT临床表型或疾病进展之间的相关性。为了开始解决这些未回答的问题，我们提出1）确定在从突变RTT诱导的多能干细胞（iPSC）分化的星形胶质细胞中甾醇代谢是否改变，以及胆固醇合成途径的操纵是否可以拯救RTT星形胶质细胞中的细胞表型;和2）对RTT患者的固醇代谢进行精细的探索，促进固醇生物标志物和临床表型之间的未来相关性。我们提出的研究结果将有助于确定RTT患者或来自这些患者的脑细胞中的固醇代谢是否改变（如RTT小鼠模型中的发现所示），并揭示这种改变在其他临床症状中的意义。如果成功，我们的研究不仅将促进我们对RTT疾病机制的理解，还将为RTT患者带来潜在的治疗方法。

 DESCRIPTION (provided by applicant) Rett syndrome (RTT) is a debilitating neurodevelopmental disorder primarily affecting females. Although it is clear that mutations in a single gene (MECP2) cause the disease, the precise mechanism underlying the pathologies is not well understood. Natural history studies of RTT patients and research using mouse models of RTT and RTT patient iPSC models have all contributed to our current understanding of the disease. Because each experimental platform has its unique strength and limitations, before insights gained on a particular platform become useful for therapy development, it is critical to validate the findings on multiple platforms acros disciplines. Recently, a suppressor screen in a RTT mouse model has identified altered cholesterol metabolism as a likely influence on disease progression, opening the door to potential intervention, since many key players in the pathway are drug targets in other unrelated diseases. However, the mouse study did not identify the cellular origin of the altered cholesterol metabolism in the brain. Two subsequent studies further demonstrated some impairment in cholesterol metabolism in the plasma and fibroblasts from RTT patients. Yet, the significance of these studies is limited because plasma cholesterol levels are not correlated with brain cholesterol homeostasis and fibroblasts are notoriously poor models of brain cells, hence leaving unanswered the question of a potential contribution of abnormal cholesterol metabolism to the pathogenesis of Rett syndrome, a widely recognized neurobiological condition. Also unanswered with these two studies is the question of a correlation between the observed cholesterol abnormalities and the RTT clinical phenotype or disease progression. To begin addressing these unanswered questions, we propose to 1) determine whether sterol metabolism is altered in astrocytes differentiated from mutant RTT induced pluripotent stem cells (iPSCs) and whether manipulation of the cholesterol synthesis pathway may rescue the cellular phenotypes in RTT astrocytes; and 2) perform a refined exploration of sterol metabolism in RTT patients facilitating future correlations between sterol biomarkers and clinical phenotypes. Results from our proposed study will help to determine whether sterol metabolism is altered in RTT patients or brain cells derived from these patients (as suggested by findings in RTT mouse models), and reveal the significance of such alteration in the context of other clinical symptoms. If successful, our study will not only advance our understanding of RTT disease mechanisms, but also lead to potential treatments for RTT patients.