Characterization of a Treatment-Response Biomarker in Patients with Schizophrenia

精神分裂症患者治疗反应生物标志物的表征

基本信息

批准号：
7936867
负责人：
JUDITH Morse GAULT
金额：
$ 49.99万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7936867
关键词：
Accounting Acute Address Aftercare Agreement Antipsychotic Agents Area Binding Bioinformatics Biological Markers Biological Markers Bipolar Disorder Blood Blood Cells Blood specimen Candidate Disease Gene Cell Line Collaborations DRD2 gene Data Development Disease Disease remission Dopamine Dopamine D2 Receptor Dose Enrollment Etiology Gene Chips Gene Expression Genes Genetic Genetic Transcription Genomics Glycogen Synthase Kinase 3 Hospitals Incubated Individual Injectable Inpatients Investigation Lead Lymphocyte Measures Mental disorders Methods Microarray Analysis Molecular Biology Monitor Outcome Pathway interactions Patients Pattern Peripheral Peripheral Blood Lymphocyte Persons Pharmaceutical Preparations Pharmacological Treatment Polymerase Chain Reaction Protein Isoforms Psychotic Disorders Relapse Research Reverse Transcription Risperidone Sampling Schizophrenia Screening procedure Serum Signaling Molecule Smoking Tail Testing Therapeutic Tissue-Specific Gene Expression Tissues Transcript Validation aged base brain tissue burden of illness disability drug metabolism innovation non-compliance novel peripheral blood prevent public health relevance response response marker tool treatment response

项目摘要

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (03): Biomarker Discovery and Validation, 03-MH- 101 Biomarkers in mental disorders. The research proposed continues investigation of a new treatment-response biomarker (antipsychotic-biomarker) identified in paired samples of lymphocytes collected from consecutively enrolled patients with schizophrenia. The first blood sample is collected after a person is being admitted to the hospital for acute psychosis. A second blood sample is collected once the patient is stable on medication. The antipsychotic-biomarker was found at high levels during acute psychosis and low levels after treatment using two methods of analysis (microarray expression analysis and quantitative reverse transcription polymerase chain reaction (qRT-PCR). The antipsychotic-biomarker is increased 3-23 fold during acute psychosis in 10 of 11 paired samples (p=0.037, using a paired T- test, 2 tailed). Relapse is a primary contributor to schizophrenia disease burden. Relapse is not entirely due to noncompliance and 27-50% of patients on injectable antipsychotic medication relapse each year into acute psychosis consistent with a need to monitor and adjust medications in accordance with a variable disease course. To date, unbiased biological markers that indicate fluctuation of disease course or markers of response to therapy do not exist. The hypothesis that the level of the antipsychotic-biomarker is decreased in lymphocytes in response to treatment with antipsychotics is tested in patients (Aim 1) and in cultured lymphocytes (Aim 2). Aim 1 is to verify differential gene expression of our novel antipsychotic-biomarker through the analysis of 42 more paired samples collected during the 2-year project period. In Aim 2 peripheral blood lymphocytes will be incubated with an antipsychotic with the intent of generating a dose response curve. Aim 3 is to verify 45 other putative treatment response biomarkers related to the same dopamine pathway using genomics and qRT-PCR. Identifying treatment-response biomarkers is the first step toward developing a tool that can be employed to optimize antipsychotic dose, predict treatment response, monitor the course of illness and ultimately prevent relapse. Treatment- response biomarkers are essential to relieving the primary burden of schizophrenia disease. PUBLIC HEALTH RELEVANCE; Progress in understanding and effectively treating diseases like schizophrenia is dependent on identifying reliable objective measures of disease in readily accessible tissues such as blood. This proposal will verify and characterize a novel gene expression biomarker of antipsychotic treatment response in patients with schizophrenia. Additional blood based biomarkers will be sought.

描述（由申请人提供）：本申请涉及广泛的挑战领域 (03)：生物标志物发现和验证，03-MH-101 精神障碍中的生物标志物。该研究建议继续研究一种新的治疗反应生物标志物（抗精神病生物标志物），该生物标志物是从连续入组的精神分裂症患者收集的成对淋巴细胞样本中发现的。第一份血样是在一个人因急性精神病入院后采集的。一旦患者的药物治疗情况稳定，就会收集第二份血样。使用两种分析方法（微阵列表达分析和定量逆转录聚合酶链反应 (qRT-PCR)）发现，在急性精神病期间，抗精神病药物生物标志物处于高水平，而在治疗后则处于低水平。在急性精神病期间，抗精神病药物生物标志物增加了 3-23 倍。 11 个配对样本中的 10 个样本中存在急性精神病（p=0.037，使用配对 T 检验，2 尾）。复发是精神分裂症的主要原因。复发并不完全是由于不依从性，每年有 27-50% 的注射抗精神病药物患者复发为急性精神病，这与根据不同的病程监测和调整药物的需要一致，迄今为止，无偏见的生物标志物。表明疾病过程或治疗反应标志物波动的情况并不存在。在患者中测试了淋巴细胞中抗精神病药物生物标志物水平因抗精神病药物治疗而降低的假设（目的）。 1) 和培养的淋巴细胞（目标 2）。目标 1 是通过分析 2 年项目期间收集的 42 个以上配对样本来验证我们的新型抗精神病药物生物标志物的差异基因表达。在 Aim 2 中，外周血淋巴细胞将与抗精神病药物一起孵育，以生成剂量反应曲线。目标 3 是使用基因组学和 qRT-PCR 验证与同一多巴胺通路相关的 45 个其他假定治疗反应生物标志物。识别治疗反应生物标志物是开发一种工具的第一步，该工具可用于优化抗精神病药物剂量、预测治疗反应、监测病程并最终预防复发。治疗反应生物标志物对于减轻精神分裂症疾病的主要负担至关重要。公共卫生相关性；理解和有效治疗精神分裂症等疾病的进展取决于在血液等容易接近的组织中确定可靠的客观疾病测量方法。该提案将验证和表征精神分裂症患者抗精神病药物治疗反应的新型基因表达生物标志物。将寻求其他基于血液的生物标志物。