PI and Wnt Signaling in Postmortem Brain of Biopolar and Schizophrenia Subjects

描述(申请人提供)：双相(BP)障碍和精神分裂症(SZ)是毁灭性的疾病，是一个主要的公共卫生问题。虽然这些疾病是独立的诊断实体，但它们有许多共同的临床特征和生物异常。在这些疾病中观察到的两个最一致的异常是信号转导机制的异常和大脑的结构异常。与这些疾病相关的两个大脑区域是前额叶皮质(RFC)和扣带回皮质。我们建议对BP障碍患者、SZ患者和正常对照组的死后脑标本的前额叶和扣带回皮质中的磷脂酰肌醇(PI)和Wnt信号通路进行全面研究。这一建议是基于一个中心假设，即信号机制的异常可能是由于这些信号通路的某些组成部分和/或由这些信号通路激活的转录因子的异常所致。简而言之，我们计划测定磷脂酶C(PLC)和蛋白激酶C(PKC)同工酶、IPs受体亚型和肉豆蔻酰化富含丙氨酸的C激酶底物(MARCKS)的蛋白和mRNA表达，这些都是PI信号系统的组成部分。我们还将测定PLC的活性，PKC和PKC介导的Marcks的磷酸化。为了研究Wnt通路在这些疾病中的作用，我们将检测Wnt信号通路的所有组成部分，即CREB、AP-1转录因子(C-Jun和C-fos)在BP和SZ受试者的PFC和扣带回皮质中的蛋白和mRNA表达，以及转录因子CREB、AP-1转录因子(C-Jun和C-FOS)的蛋白和mRNA表达。如果主要信号通路PI和WnT的异常与BP和SZ的病理生理相关，这些研究将提供全面的信息。这可能最终会使我更好地了解BP或SZ疾病的病理生理学，并可能有助于开发更合适的治疗药物来治疗这些疾病。

DESCRIPTION (provided by applicant): Bipolar (BP) disorder and schizophrenia (SZ) are devastating illnesses and are a major public health concern. Although these illnesses are separate diagnostic entities, they share many common clinical features and biological abnormalities. The two most consistent abnormalities observed in these illnesses are the abnormalities in the signal transduction mechanisms and the structural abnormalities in the brain. The two brain areas often implicated in these disorders are the prefrontal cortex (RFC) and the cingulate cortex. We are proposing a comprehensive study of phosphoinositide (PI) and Wnt signaling pathways in the prefrontal and cingulate cortex of postmortem brain samples obtained from subjects with BPdisorders, SZ and normal control subjects. This proposal is based on a central hypothesis that the abnormalities in the signaling mechanisms may be specifically due to abnormalities in some components of these signaling pathways and/or transcription factors activated by these pathways. Briefly, we plan to determine the protein and mRNA expression of phospholipase C (PLC) and protein kinase C (PKC) isozymes, IPs receptor subtypes, and myristoylated alanine-rich C kinase substrate (MARCKS), components of the PI signaling system. We will also determine the activity of PLC, PKC anc PKC-mediated phosphorylation of MARCKS. To examine the role ofthe Wnt pathway in these disorders, we will determine protein and mRNA expression of Disheveled, GSK-3P and p-catenin, all components of the Wnt signaling pathway, protein and mRNA expression and DNA binding of transcription factors, namely, CREB, AP-1 transcription factors (C-Jun and C-fos) in the PFC and cingulate cortex of BP and SZ subjects. These studies will provide comprehensive information if abnormalities in the major signaling pathways namely, PI and Wnt, are associated with the pathophysiology of BP and SZ. This may eventually lead to i better understanding of the pathophysiology of BP or SZ illnesses and may aid in the development of more appropriate therapeutic agents for the treatment of these disorders.