Epigenetic Markers For Development of Schizophrenia

精神分裂症发展的表观遗传标记

基本信息

批准号：
8720065
负责人：
ALESSANDRO GUIDOTTI
金额：
$ 19.74万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-12 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8720065
关键词：
Acids Addendum Affect Appearance Autistic Disorder Base Excision Repairs Binding Binding Proteins Biochemical Biological Markers Bipolar Disorder Brain Brain-Derived Neurotrophic Factor California Candidate Disease Gene China Chinese People Chromatin Chronic Schizophrenia Cytidine Deaminase Cytosine DNA DNA Damage DNA Methylation DNA Methyltransferase DNA Modification Methylases DSM-IV Data Deaminase Development Disease Early Intervention Enzymes Epigenetic Process Figs - dietary Functional disorder GADD45 GADD45 protein Genes Genetic Genetic Transcription Glucocorticoid Receptor Goals Health Illinois Individual Island Lymphocyte Measures Messenger RNA Methylation Mitotic Mixed Function Oxygenases Molecular Conformation Multicenter Studies Neurons Pathology Pathway interactions Patients Process Promoter Regions Protein translocation Proteins Psychotic Disorders Receptor Gene Recruitment Activity Research Research Personnel Research Support Role Schizophrenia Symptoms Thymidine Universities cohort demethylation epigenetic marker first episode schizophrenia follow-up gamma-Aminobutyric Acid high risk mRNA Expression meetings neuropsychiatry outcome forecast promoter psychotic symptoms public health relevance repair enzyme

项目摘要

DESCRIPTION (provided by applicant): The goal of this proposed research is to determine whether differences in the expression of epigenetic related biomarkers are present in lymphocytes of people with genetic high risk and/or prodromal symptoms of schizophrenia (HRSK subjects) as previously found in lymphocytes of chronic schizophrenia (SZ) patients. We will also assess whether the presence of these biomarkers predicts which HRSK subjects will progressively develop more psychotic symptoms over a two year period and who will convert from HRSK status to first episode schizophrenia or another diagnosable psychotic disorder. Investigators on this proposal, have been collaborating with a group of investigators in Hunan, China for several years (Wu et al., 2008; 2012). The China group is currently conducting a multi-center study supported by the Chinese Ministry of Health that involves 5000 HRSK and 2000 control subjects. The research we are proposing would be an addendum to this larger study. DNA methylation and demethylation are key epigenetic components involved in orchestrating transcription of specific genes in post mitotic neurons (Guidotti et al., 2011). It has been suggested that the DNA methylation/demethylation process is perturbed in neuropsychiatric disorders such as schizophrenia (SZ), bipolar disorder (BP), and autism. We have shown that abnormalities in some of these epigenetic marks in the brain of SZ patients are also present in their lymphocytes. Lymphocytes of SZ patients have higher DNMT1 mRNA expression than non-psychotic controls (Zhubi et al 2009), higher levels of other methylating and demethylating enzymes (growth arrest and DNA damage-inducible protein [GADD45] and ten-eleven translocation protein [TET]), and lower levels of glucocorticoid receptor and GAD67 mRNA (preliminary data). If differences in these potential epigenetic biomarkers can be confirmed in lymphocytes of HRSK subjects, some of the underlying biochemical developmental pathology leading to SZ might be uncovered. This result could provide epigenetic biomarkers useful in predicting which HRSK subjects are more likely to develop full symptoms of SZ or a related psychosis. Identifying potential biomarkers would have implications for prognosis and identifying patients who would be most likely to benefit from intensive early intervention and specialized treatment. This background leads us to pursue three Specific Aims for the current proposed study: AIM1: Measure the expression level of DNA methylation related genes in lymphocytes of HRSK subjects at baseline compared to controls and first episode and chronic SZ patients. AIM 2: Determine whether epigenetic chromatin status and the expression of SZ candidate genes is regulated by the binding of proteins that are constituents of the DNA- methylation/demethylation pathways in lymphocytes of HRSK subjects at baseline compared to controls and first episode and chronic SZ patients. AIM 3 Determine whether HRSK subjects who also have epigenetic lymphocyte abnormalities at baseline are more likely to progress to more severe psychotic-like symptoms or convert to diagnosable psychotic status during a two year follow up. This proposed research is potentially a major step toward the identification of objective biomarkers capable of predicting conversion to psychosis in HRSK subjects.

描述（由申请人提供）：这项拟议的研究的目的是确定在具有遗传高风险和/或精神分裂症患者（HRSK受试者）的淋巴细胞中是否存在表观遗传学相关生物标志物表达的差异（HRSK受试者）慢性精神分裂症（SZ）患者的淋巴细胞。我们还将评估这些生物标志物的存在是否可以预测哪些HRSK受试者将在两年内逐渐发展出更多的精神病症状，并且谁将从HRSK状态转变为第一事件精神分裂症或其他可诊断的精神病疾病。关于该提案的研究人员已经与中国湖南的一组研究人员合作了几年（Wu等，2008; 2012）。中国集团目前正在进行一项由中国卫生部支持的多中心研究，其中涉及5000 hrsk和2000个对照对象。我们提出的研究将是这项大型研究的附录。 DNA甲基化和脱甲基化是涉及有丝分裂神经元特定基因转录的关键表观遗传成分（Guidotti等，2011）。已经提出，DNA甲基化/去甲基化过程在精神分裂症（SZ），双相情感障碍（BP）和自闭症等神经精神疾病中受到干扰。我们已经表明，SZ患者大脑中某些表观遗传标记的异常也存在于其淋巴细胞中。 SZ患者的淋巴细胞具有比非精神病对照更高的DNMT1 mRNA表达（Zhubi等，2009年），其他甲基化和脱甲基化酶的水平更高（生长停滞和DNA损伤诱导蛋白[GADD45]和十个时期的易受影响蛋白[TET] [TET] [TET] ），糖皮质激素受体和GAD67 mRNA的水平较低（初步数据）。如果在HRSK受试者的淋巴细胞中可以证实这些潜在的表观遗传生物标志物的差异，则可能会发现一些导致SZ的基本生化发育病理学的差异。该结果可能会提供表观遗传生物标志物，可用于预测哪些HRSK受试者更可能出现SZ或相关精神病的全部症状。识别潜在的生物标志物将对预后有影响，并确定最有可能受益于强化早期干预和专业治疗的患者。这种背景使我们针对当前提出的研究实现了三个特定目标：AIM1：与对照组，第一发以及慢性SZ患者相比，基线时HRSK受试者淋巴细胞中DNA甲基化相关基因的表达水平。目标2：确定表观遗传染色质状态和SZ候选基因的表达是否受到蛋白质的结合，这是基础和第一发和慢性SZ患者相比，基线时HRSK受试者淋巴细胞中HRSK受试者淋巴细胞中DNA-甲基化/脱硫途径的结合。 AIM 3确定在基线时也患有表观遗传淋巴细胞异常的HRSK受试者是否更有可能在两年内进行更严重的精神病样症状或转化为可诊断的精神病状态。这项拟议的研究可能是迈向鉴定能够预测HRSK受试者精神病的客观生物标志物迈出的重大步骤。