Extracellular anomalies in Schizophrenia: from molecules to symptoms

精神分裂症的细胞外异常：从分子到症状

• 批准号: 8811470
• 负责人: Sabina Berretta
• 金额: $ 53.77万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-26 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8811470
• 关键词: Adult; Affect; Astrocytes; Autopsy; Axon; Biological; Biological Markers; Biopsy; Bipolar Disorder; Brain region; Carrier Proteins; Cell Count; Cell Culture Techniques; Cells; Chondroitin; Chondroitin Sulfate Proteoglycan; Clinical; Clinical Research; Data; Defect; Development; Diagnosis; Disease; Down-Regulation; Extracellular Matrix; Fiber; Fibroblasts; Functional disorder; Goals; Human; Immigration; In Vitro; Investigation; Life; Link; Maintenance; Measures; Medial; Membrane; Messenger RNA; Metabolism; Molecular; Morphology; Nervous system structure; Neuraxis; Neuroglia; Neurons; Neurophysiology - biologic function; Olfactory Epithelium; Olfactory Pathways; Pathway interactions; Principal Investigator; Psychotic Disorders; RNA Interference; Recording of previous events; Regulation; Research; Role; Schizophrenia; Severities; Signal Pathway; Skin; Specificity; Structural defect; Structure; Symptoms; Synapses; Temporal Lobe; Testing; Tissues; Transforming Growth Factors; Ursidae Family; Work; clinical investigation; cohort; design; extracellular; in vitro Model; in vitro testing; mRNA Expression; migration; olfactory bulb; olfactory bulb glomeruli; programs; receptor; relating to nervous system

DESCRIPTION (provided by applicant): Recent findings from our group point to substantial abnormalities affecting the extracellular matrix (ECM) in medial temporal regions of subjects with schizophrenia, but not bipolar disorder. Our data points to anomalous expression of chondroitin sulfate proteoglycans (CSPGs), a main component of the ECM, in glial cells and ECM. CSPG functions during development and adulthod, such as regulation of neuronal migration, axon outgrowth, stabilization of synaptic connectivity, maintenance of neuronal networks and neuronal microenvironment, bear direct relevance to the pathophysiology of schizophrenia. Preliminary results suggest that similar abnormalities occur in the olfactory epithelium (OE) and olfactory bulb (OB), as well as peripherally in skin fibroblasts, of subjects with SZ. Investigations on ECM abnormalities in the olfactory system (OE and OB), as proposed here, offer compelling advantages. First, neurodevelopmental functions such as neuron diferentiation, migration in OE, and axon outgrowth toward OB, occur throughout life, alongside adult neural functions, making the olfactory system ideally suited for investigations on CSPGs. Second, growing evidence for olfactory deficits in SZ, particularly in association with negative symptoms, renders investigations on the olfactory system directly relevant to the clinical manifestations of this disease. Third, the OE is the only central nervous system structure easily accessible by biopsy, from which cel cultures can be developed. The main goal of these studies is to investigate the relationship between the pathophysiology of CSPG abnormalities in schizophrenia and clinical manifestations of this disease. The potential for CSPG abnormalities to represent a biological marker with pathophysiological relevance and specificity for schizophrenia will be assessed in the context of specific hypotheses on the mechanisms of ECM abnormalities and their association with core symptoms of this disease. The main hypothesis tested is that ECM abnormalities, due to a disruption of molecular pathways regulating CSPG synthesis and secreti0n, affect the olfactory system in subjects with SZ and can be detected peripherally. We postulate that such abnormalities may be associated with specific olfactory deficits and negative symptoms. To test this hypothesis, CSPG abnormalities will be assessed in OE and skin fibroblasts (biopsy/in vitro), as well as the OB (postmortem), from two cohorts of normal control, SZ and BD subjects. Human fibroblast and OE primary cultures obtained from skin and OE biopsies, respectively, will be used to test, in vitro, diagnosis effects on the molecular mechanisms regulating CSPG expression. Biopsy donors will be tested for olfactory functions and on psychiatric rating scales. BD subjects will be included to test whether CSPG abnormalities are specific to SZ or represent a shared feature among major psychoses.

描述（由申请人提供）：我们小组的最新研究结果表明，精神分裂症患者的内侧颞区细胞外基质（ECM）存在显着异常，但双相情感障碍患者则不然。我们的数据表明，硫酸软骨素蛋白聚糖（CSPG）是 ECM 的主要成分，在神经胶质细胞和 ECM 中存在异常表达。 CSPG 在发育和成年期间的功能，例如调节神经元迁移、轴突生长、稳定突触连接、维持神经元网络和神经元微环境，与精神分裂症的病理生理学直接相关。初步结果表明，SZ 患者的嗅上皮 (OE) 和嗅球 (OB) 以及外周皮肤成纤维细胞中也出现类似的异常。正如本文所建议的，对嗅觉系统（OE 和 OB）ECM 异常的研究具有令人信服的优势。首先，神经发育功能，如神经元分化、OE 中的迁移和轴突向 OB 的生长，与成人神经功能一起发生在整个生命周期，使得嗅觉系统非常适合研究 CSPG。其次，越来越多的证据表明 SZ 存在嗅觉缺陷，特别是与阴性症状相关，使得对嗅觉系统的研究与该疾病的临床表现直接相关。第三，OE是唯一易于通过活检获得的中枢神经系统结构，从中可以开发细胞培养物。这些研究的主要目的是探讨精神分裂症 CSPG 异常的病理生理学与该疾病的临床表现之间的关系。 CSPG 异常代表精神分裂症具有病理生理学相关性和特异性的生物标志物的潜力将在关于 ECM 异常机制及其与该疾病核心症状的关联的具体假设的背景下进行评估。测试的主要假设是，由于调节 CSPG 合成和分泌的分子途径的破坏，ECM 异常会影响 SZ 受试者的嗅觉系统，并且可以在外周检测到。我们假设这种异常可能与特定的嗅觉缺陷和阴性症状有关。为了检验这一假设，将对两组正常对照（SZ 和 BD 受试者）的 OE 和皮肤成纤维细胞（活组织检查/体外）以及 OB（尸检）中的 CSPG 异常进行评估。分别从皮肤和 OE 活检中获得的人成纤维细胞和 OE 原代培养物将用于体外测试对调节 CSPG 表达的分子机制的诊断效果。活检捐献者将接受嗅觉功能和精神病评定量表的测试。 BD 受试者将被纳入测试，以测试 CSPG 异常是否是 SZ 所特有的，或者是否代表了主要精神病的共同特征。

项目成果

What can we learn about brain donors? Use of clinical information in human postmortem brain research.

关于大脑捐赠者，我们能了解到什么？

• 发表时间: 2018
• 作者: Sullivan, Kathleen;Pantazopoulos, Harry;Liebson, Elizabeth;Woo, T;Baldessarini, Ross J;Hedreen, John;Berretta, Sabina
• 通讯作者: Berretta, Sabina