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

双相情感障碍和精神分裂症受试者死后大脑中的 PI 和 Wnt 信号转导

• 批准号: 7211873
• 负责人: Ghanshyam N Pandey
• 金额: $ 34.88万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-28 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7211873
• 关键词: Agonist; Area; Autopsy; Biological; Bipolar Disorder; Blood Platelets; Brain; Brain-Derived Neurotrophic Factor; Cells; Clinical; Cyclic AMP-Responsive DNA-Binding Protein; Cytosol; DNA Binding; Data; Development; Diagnostic; Disease; Event; Functional disorder; Genes; Genetic Transcription; Glycogen Synthase Kinase 3; Isoenzymes; Lead; Link; Lithium; Lymphocyte; Mediating; Membrane; Messenger RNA; Moods; Neurobiology; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Phosphatidylinositols; Phospholipase C; Phosphorylation; Prefrontal Cortex; Principal Investigator; Protein Kinase C; Proteins; Public Health; Purpose; Research Personnel; Role; Sampling; Schizophrenia; Signal Pathway; Signal Transduction; Suggestion; System; Therapeutic Agents; Transcription Factor AP-1; activating transcription factor; base; cingulate cortex; citrate carrier; factor C; inositol-1,4,5-triphosphate receptor; mRNA Expression; myristoylated alanine-rich C kinase substrate; novel; programs; protein expression; receptor; transcription factor

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.

描述（由申请人提供）：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，但它们具有许多共同的临床特征和生物学异常。在这些疾病中观察到的两种最一致的异常是信号转导机制的异常和大脑结构的异常。通常与这些疾病有关的两个大脑区域是前额叶皮层（RFC）和扣带皮层。我们提出了一个全面的研究磷脂酰肌醇（PI）和Wnt信号通路的前额叶和扣带皮层的尸检脑样本与BPdisorders，SZ和正常对照组的主题。这一建议是基于一个中心假设，即信号传导机制的异常可能是由于这些信号传导途径的某些组分和/或由这些途径激活的转录因子的异常所致。简而言之，我们计划确定磷脂酶C（PLC）和蛋白激酶C（PKC）同工酶，IP受体亚型和豆蔻酰丙氨酸丰富的C激酶底物（MARCKS），PI信号系统的组件的蛋白质和mRNA的表达。我们还将测定PLC、PKC和PKC介导的MARCKS磷酸化的活性。为了研究Wnt通路在这些疾病中的作用，我们将测定BP和SZ受试者PFC和扣带回皮质中Disheveled、GSK-3 P和β-连环蛋白的蛋白和mRNA表达、Wnt信号通路的所有组分、转录因子的蛋白和mRNA表达以及DNA结合，即CREB、AP-1转录因子（C-Jun和C-fos）。这些研究将提供全面的信息，如果异常的主要信号通路，即PI和Wnt，与BP和SZ的病理生理学。这可能最终导致更好地理解BP或SZ疾病的病理生理学，并可能有助于开发用于治疗这些疾病的更合适的治疗剂。