Sterol metabolism in Rett syndrome

雷特综合征中的甾醇代谢

基本信息

批准号：
9206170
负责人：
Qiang Chang
金额：
$ 8.38万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-15 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9206170
关键词：
7-dehydrocholesterol Address Affect Astrocytes Biological Markers Brain California Cell Line Cell model Cells Cholesterol Cholesterol Homeostasis Clinic Clinical Collaborations Data Development Discipline Disease Disease Progression Drug Targeting Electronic Health Record Female Fibroblasts Future Genes Genetic Human Hydroxycholesterols Impairment Intervention Knowledge Laboratories Lead Link Metabolism Methyl-CpG-Binding Protein 2 Modeling Morphology Mus Mutation Natural History Nervous system structure Neurobiology Neurodevelopmental Disorder Neurons Outcome Pathogenesis Pathology Pathway interactions Patient Recruitments Patients Pharmacology Phenotype Plasma Play Protocols documentation Reporting Research Resources Rett Syndrome Role Sterols Symptoms Universities Variant brain cell cell type clinical phenotype cohort congenic disease-causing mutation experimental study induced pluripotent stem cell insight lathosterol mouse model mutant neurodevelopment neuron development novel therapeutics public health relevance screening sterol homeostasis synaptogenesis therapy development

项目摘要

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.

描述（由申请人提供） RETT综合征（RTT）是一种令人衰弱的神经发育障碍，主要影响女性。尽管很明显，单个基因中的突变（MECP2）引起该疾病，但病理学的确切机制尚不清楚。 RTT患者的自然历史研究和使用RTT和RTT患者IPSC模型的小鼠模型进行研究都有助于我们当前对疾病的理解。由于每个实验平台都有其独特的力量和局限性，在对治疗开发有用的特定平台上获得的见解之前，至关重要的是，在跨学科的多个平台上验证结果至关重要。最近，RTT小鼠模型中的抑制剂筛查已确定改变的胆固醇代谢可能会影响疾病进展，为潜在的干预打开大门，因为该途径中的许多关键参与者都是其他无关疾病的药物靶标。但是，小鼠研究并未鉴定出大脑中胆固醇代谢改变的细胞起源。随后的两项研究进一步证明了血浆中胆固醇代谢和RTT患者成纤维细胞的一些损害。然而，这些研究的意义受到限制，因为血浆胆固醇水平与脑胆固醇稳态无关，而成纤维细胞是众所周知的脑细胞模型较差的模型，因此，毫无疑问，毫无疑问，胆固醇代谢代谢对Rett综合征的病原体的潜在贡献的问题，一种广泛的Neurobiolobipic neurobiogical，是一种广泛的脑细胞。这两项研究也没有得到答复，这是观察到的胆固醇异常与RTT临床表型或疾病进展之间存在相关性的问题。为了开始解决这些未解决的问题，我们建议1）确定在与突变体RTT诱导的多能干细胞（IPSC）区分的星形胶质细胞中是否改变了固醇代谢，以及胆固醇合成途径的操纵是否可以挽救RTT Atrococytes中的细胞表型； 2）在RTT患者中对立体代谢进行了精致的探索，该患者支持立体生物标志物与临床表型之间的未来相关性。我们拟议的研究的结果将有助于确定在RTT患者或从这些患者中得出的脑细胞中的立体代谢（如RTT小鼠模型中的发现）是否改变了，并揭示了这种改变在其他临床症状中的重要性。如果成功，我们的研究不仅会提高我们对RTT疾病机制的理解，还可以为RTT患者带来潜在的治疗方法。