Gene expression and functional studies from olfactory neurons of bipolar disorder

双相情感障碍嗅觉神经元的基因表达和功能研究

• 批准号: 8443800
• 负责人: Koko Ishizuka
• 金额: $ 23.33万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-15 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8443800
• 关键词: Address; Affect; Applications Grants; Biopsy; Biopsy Specimen; Bipolar Disorder; Brain; Categories; Cells; Characteristics; Cilia; Clinical; Cognitive deficits; Data; Development; Diagnosis; Disease; Disease Pathway; Exhibits; Future; Gene Expression; Genes; Genetic; Genome; Head; Human; Mental disorders; Methodology; Modeling; Molecular; Molecular Profiling; Mood Disorders; Neuraxis; Neurons; Nose; Olfactory Epithelium; Pathology; Pathway interactions; Patients; Phosphorylation; Physiologic pulse; Predisposition; Protocols documentation; Psyche structure; Psychiatry; Public Health; Recruitment Activity; Research; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Schizophrenia; Serine; Severities; Signal Transduction; Staging; Susceptibility Gene; Technology; base; disability; disorder control; insight; neurodevelopment; programs; sample collection; stem

DESCRIPTION (provided by applicant): Bipolar disorder (BP) is among the most important public health problems in the world and is one of the top ten leading causes of lifelong disability Recent large-scale collaborative sample collections along with rapid advances in genome technology are poised to provide statistical evidence of association and/or linkage, but mechanistic understanding of the disease remains at an initial stage. One major limitation that has blocked the progress, although mental disorders such as BP and schizophrenia affect the brain, is the difficulty in accessing neuronal cells from patients. To overcome this dilemma, we have optimized a protocol to enrich olfactory immature neurons from nasal biopsied samples from humans. We previously utilized this methodology to study molecular and cellular profiles of patients with schizophrenia (SZ) and normal controls. Here in this proposal, we plan to use the olfactory epithelium immature neurons (OE neurons) from subjects with psychotic BP, which is familiarly associated with SZ and shares many endophenotypic abnormalities, such as greater severity of cognitive deficits and impaired pre-pulse inhibition. Thus, we hypothesize that such shared abnormalities may stem from molecular and cellular deficits associated with neurodevelopment. To address this hypothesis, we will newly recruit 30 subjects with psychotic and non-psychotic BP, and enrich OE neurons (Aim 1). By using these cells, we will determine development-associated deficits, with an emphasis on Wnt pathway and developmental switch of phospho-DISC1, in psychotic BP. The data will be compared with those from OE neurons from patients with schizophrenia, non-psychotic BP, and normal controls (Aim 2). Then, we will identify gene expression profiles related to Wnt signaling/cilia formation pathways in OE neurons from patients with psychotic BP, in comparison with those from patients with schizophrenia, non-psychotic BP, and controls (Aim 3). This study has the potential to provide important insight into the molecular and cellular signature of psychotic BP associated with neurodevelopment. We expect that some of the major changes may be shared with those in schizophrenia, which contribute to the further study of common susceptibility mechanisms for these disorders.

描述（由申请人提供）：双相情感障碍（BP）是世界上最重要的公共卫生问题之一，也是终身残疾的十大主要原因之一。随着基因组技术的迅速发展，最近的大规模合作样本收集沿着准备提供关联和/或联系的统计证据，但对该疾病的机制理解仍处于初始阶段。尽管BP和精神分裂症等精神疾病会影响大脑，但阻碍进展的一个主要限制是难以获得患者的神经元细胞。为了克服这一困境，我们优化了一个协议，以丰富嗅觉未成熟的神经元从鼻腔活检样本从人类。我们以前利用这种方法来研究精神分裂症（SZ）患者和正常对照的分子和细胞谱。在这个建议中，我们计划使用来自精神病性BP受试者的嗅上皮未成熟神经元（OE神经元），这与SZ密切相关，并具有许多内表型异常，例如更严重的认知缺陷和受损的前脉冲抑制。因此，我们推测这种共同的异常可能源于与神经发育相关的分子和细胞缺陷。为了解决这一假设，我们将新招募30名患有精神病和非精神病BP的受试者，并富集OE神经元（目的1）。通过使用这些细胞，我们将确定发育相关的缺陷，重点是Wnt途径和磷酸化DISC 1的发育开关，在精神病性BP。将这些数据与来自精神分裂症患者、非精神病性BP患者和正常对照的OE神经元的数据进行比较（目的2）。然后，我们将确定与精神病性BP患者OE神经元中Wnt信号传导/纤毛形成途径相关的基因表达谱，并与精神分裂症患者、非精神病性BP患者和对照组进行比较（目的3）。这项研究有可能提供重要的洞察与神经发育相关的精神病性BP的分子和细胞特征。我们期望一些主要的变化可能与精神分裂症的变化相同，这有助于进一步研究这些疾病的共同易感性机制。