Gene expression and functional studies from olfactory neurons of bipolar disorder

描述(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，也是导致终身残疾的十大主要原因之一。最近，随着基因组技术的快速进步，大规模的合作样本收集有望提供关联和/或关联的统计证据，但对这种疾病的机械论理解仍处于初始阶段。尽管BP和精神分裂症等精神障碍会影响大脑，但阻碍这一进展的一个主要限制是很难接触到患者的神经细胞。为了克服这一困境，我们优化了一种从人类鼻部活检样本中丰富嗅觉未成熟神经元的方案。我们以前使用这种方法研究了精神分裂症(SZ)患者和正常对照组的分子和细胞图谱。在这项提议中，我们计划使用来自精神病型BP受试者的嗅觉上皮未成熟神经元(OE神经元)，这种神经细胞与SZ密切相关，并具有许多内表型异常，如更严重的认知缺陷和受损的脉冲前抑制。因此，我们假设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，并丰富OE神经元(目标1)。通过使用这些细胞，我们将确定精神病BP中与发育相关的缺陷，重点是Wnt途径和磷酸化DISC1的发育开关。这些数据将与来自精神分裂症患者、非精神病性BP患者和正常对照组的OE神经元的数据进行比较(目标2)。然后，我们将确定与Wnt信号/纤毛形成途径相关的基因表达谱，来自精神病BP患者的OE神经元与精神分裂症患者、非精神病BP患者和对照组(目标3)进行比较。这项研究有可能为精神病性BP与神经发育相关的分子和细胞特征提供重要的见解。我们预计，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常见易感机制。

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.