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）雷特综合征 (RTT) 是一种主要影响女性的衰弱性神经发育障碍，尽管很明显单基因 (MECP2) 突变会导致该疾病，但对 RTT 患者的自然史研究和研究尚不清楚其病理学的确切机制。使用 RTT 小鼠模型和 RTT 患者 iPSC 模型都有助于我们目前对该疾病的理解，因为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，验证至关重要。多项调查结果最近，RTT 小鼠模型中的抑制筛选发现胆固醇代谢的改变可能对疾病进展产生影响，这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都是其他不相关疾病的药物靶标。小鼠研究并未确定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 RTT 患者血浆和成纤维细胞中胆固醇代谢的某些损害，但这些研究的意义有限，因为血浆胆固醇水平较高。与脑胆固醇无关稳态和成纤维细胞是众所周知的较差的脑细胞模型，因此，胆固醇代谢异常对雷特综合征（一种广泛认可的神经生物学疾病）发病机制的潜在贡献的问题尚未得到解答，这两项研究也未解答以下问题：观察到的胆固醇异常和 RTT 临床表型或疾病进展为了开始解决这些未解答的问题，我们建议 1) 确定由突变 RTT 诱导分化的星形胶质细胞中甾醇代谢是否发生改变。多能干细胞（iPSC）并操纵胆固醇合成途径是否可以挽救RTT星形胶质细胞的细胞表型；2）对RTT患者的甾醇代谢进行精细探索，以促进甾醇生物标志物与我们提出的临床表型之间的未来相关性。研究将有助于确定 RTT 患者或源自这些患者的脑细胞中的甾醇代谢是否发生改变（如 RTT 小鼠模型中的发现所示），并揭示这种改变在其他临床背景下的重要性如果成功，我们的研究不仅将增进我们对 RTT 疾病机制的理解，还将为 RTT 患者带来潜在的治疗方法。