MicroRNAs as Biomarkers in First-episode Schizophrenia

该指导患者导向研究职业发展奖（K23）的目标是为申请人提供必要的培训和支持，使其成为精神分裂症microRNA（miRNA）研究领域的独立研究者。由于其能够同时调节多个信使RNA的翻译，miRNA越来越多地用作医学研究中的生物标记物。在精神病学领域，一些研究已经发现某些miRNAs（如miR-137和miR-132）与精神分裂症诊断之间存在关联。然而，所有研究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，考虑到脑和脑脊液之间的密切关系，使用脑脊液来研究miRNA在精神分裂症中的作用是合乎逻辑和令人感兴趣的。因此，申请人提出研究与健康对照相比，首发精神分裂症患者的脑脊液中的miRNA表达谱。对于这一提议， 申请人计划招募已经接触抗精神病药物少于16周并且开始使用利培酮进行手动治疗的首次发作患者，作为他们在专门治疗首次发作精神分裂症患者的诊所登记的一部分。对于这些受试者，将在入组时进行腰椎穿刺。每周进行一次精神病理学和副作用评估，持续4周，然后每两周进行一次，直至患者完成16周的利培酮治疗。本申请的主要目的是：1）在来自首次发作患者和健康志愿者的脑脊液样品中进行miRNA测序，以测试在首次发作精神分裂症中显著数量的miRNA将失调的假设; 2）确定某些miRNA是否可以作为与治疗反应和/或副作用（特别是体重增加）的发展相关的预测生物标志物。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有关miRNA的分子生物学，miRNA作为预测生物标志物的使用以及用于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，优秀的导师团队加上机构资源将使申请人成为一名成功的独立研究者，拥有精神分裂症miRNA研究的专业知识。这与NIH招募更多参与转化研究的医生科学家的目标一致。

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.