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

• 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
• 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

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）：此申请涉及广泛的挑战领域（03）：生物标志物发现与验证，03-MH-101精神障碍生物标志物。该研究提出，继续研究了一种新的治疗反应生物标志物（抗精神病生标志物），这些生物标志物（抗精神病生标志物）在从连续入学的精神分裂症患者中收集的淋巴细胞的配对样品中鉴定出来。在一个人被送往医院急性精神病之后，收集了第一个血液样本。一旦患者在药物治疗中稳定，就收集了第二个血液样本。在急性精神病期间，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））在急性精神病和治疗后较低水平的抗精神病生生物标志物（QRT-PCR）。抗精神病药物 - 异构标记物在11次配对的2次配对的速度相关式A中，抗精神病药物 - 生物标志物增加了3-23倍，在10次配对的过程中增加了距离。精神分裂症疾病负担的贡献并不完全是由于不合规性和27-50％的患者，每年可注射的抗精神病药物复发到急性精神病中，与迄今为止无与伦比的生物学标志物相关的疾病或疾病的疾病疗效，在患者（AIM 1）和培养的淋巴细胞中测试了淋巴细胞的抗精神病药 - 淋巴细胞降低（AIM 2）。 AIM 1是通过分析在2年项目期间收集的42个配对样品，来验证我们新型抗精神病生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一起孵育，目的是产生剂量反应曲线。 AIM 3是使用基因组学和QRT-PCR验证45个与同一多巴胺途径相关的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可以使用该工具来优化抗精神病药剂量，预测治疗反应，监测疾病进程并最终防止复发的工具的第一步。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方面的进展取决于鉴定可靠的可及性组织（如血液）中可靠的疾病客观测量。该建议将验证并表征精神分裂症患者抗精神病药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。