MicroRNAs as Biomarkers in First-episode Schizophrenia

描述(由申请者提供)：这项以患者为导向的研究职业发展奖(K23)的目标是为申请者提供必要的培训和支持，使其成为精神分裂症微RNA(MiRNA)研究领域的独立研究员。由于miRNAs能够同时调节多个信使RNA的翻译，因此在医学研究中越来越多地被用作生物标记物。在精神病学领域，一些研究发现某些miRNAs，如miR-137和miR-132，与精神分裂症的诊断有关。然而，所有检测miRNA表达谱的人类研究都是在死后脑组织或外周血中进行的。然而，鉴于脑和脑脊液之间的密切关系，使用脑脊液来研究miRNAs在精神分裂症中的作用是合乎逻辑和耐人寻味的，因此，申请人建议与健康对照组比较，研究首发精神分裂症患者脑脊液中miRNA的表达谱。对于这项提议， 申请者计划招募接触抗精神病药物不到16周，并开始使用利培酮进行手动治疗的首发患者，作为他们在一家专门治疗首发精神分裂症患者的诊所注册的一部分。对于这些受试者，在注册时将进行腰椎穿刺术。精神病理学和副作用评估将每周进行一次，持续4周，然后每两周进行一次，直到患者完成16周的利培酮治疗。这项应用的主要目的是：1)对首发患者和健康志愿者的脑脊液样本进行miRNA测序，以验证大量miRNAs在首发精神分裂症患者中会受到失调的假设；2)确定某些miRNAs是否可以作为预测生物标记物，与治疗反应和/或副作用，尤其是体重增加有关。为了实现这些目标，已经准备了一个全面的教学计划，以帮助主要研究人员获得关于miRNAs的分子生物学、miRNAs作为预测生物标记物的使用以及用于miRNA测序数据分析的先进统计方法的知识。完成拟议的研究、本申请中描述的培训活动、杰出的指导团队以及机构资源将使申请者能够成为一名成功的独立调查员，拥有精神分裂症的miRNA研究专业知识。这与NIH招募更多参与转化研究的内科科学家的目标是一致的。

DESCRIPTION (provided by applicant): The goal of this Mentored Patient Oriented Research Career Development Award (K23) is to provide the applicant with the training and support necessary to become an independent investigator in the field of microRNA (miRNA) research in schizophrenia. MiRNAs are increasingly used as biological markers in medical research due to their capacity to simultaneously regulate the translation of multiple messenger RNAs. In the field of psychiatry, several studies have found associations between certain miRNAs, such as miR-137 and miR-132, and schizophrenia diagnosis. However, all human studies that have examined miRNA expression profiles have done so in post-mortem brain tissue or peripheral blood. However, given the intimate relationship between brain and cerebrospinal fluid, the use of cerebrospinal fluid to investigate the role of miRNAs in schizophrenia is logical and intriguing Therefore, the applicant proposes to investigate miRNA expression profiles in cerebrospinal fluid in first-episode schizophrenia patients in comparison to healthy controls. For this proposal, the applicant plans to recruit first-episode patients who have been exposed to antipsychotics for less than 16 weeks and who are initiating manualized treatment with risperidone as part of their enrollment in a clinic specialized in treatment of first-episode schizophrenia patients. For these subjects, a lumbar puncture will be obtained upon enrollment. Psychopathology and side effect assessments will be conducted weekly for 4 weeks and then every two weeks until patients complete 16 weeks of risperidone treatment. The primary aims for this application are: 1) to conduct miRNA sequencing in cerebrospinal fluid samples from first-episode patients and healthy volunteers to test the hypothesis that significant number of miRNAs will be dysregulated in first-episode schizophrenia; 2) To determine whether certain miRNAs can help as predictive biomarkers in relationship to treatment response and/or development of side effects, especially weight gain. To accomplish these aims, a comprehensive didactic program has been prepared to help the primary investigator gain knowledge about the molecular biology of miRNAs, the use of miRNAs as predictive biomarkers and the advanced statistical methods used for miRNA sequencing data analysis. The completion of the proposed study, the training activities described in this application, the outstanding mentorship team plus the institutional resources will allow the applicant to become a successful independent investigator, with expertise in miRNA research in schizophrenia. This is in alignment with the NIH goal of recruiting more physician scientists involved in translational research.