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: 8268362
• 负责人: Sabina Berretta
• 金额: $ 64.61万
• 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 2016-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8268362
• 关键词: Adult; Affect; Astrocytes; Autopsy; Axon; Biological; Biological Markers; Biological Markers; Biopsy; Bipolar Disorder; Brain region; Carrier Proteins; Cell Count; Cell Culture Techniques; Cells; Chondroitin; Chondroitin Sulfate Proteoglycan; Clinical; Clinical Research; Clinical Trials; 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; Structure; Symptoms; Synapses; System; Temporal Lobe; Testing; Tissues; Transforming Growth Factors; Ursidae Family; Work; cohort; design; extracellular; in vitro Model; in vitro testing; mRNA Expression; migration; olfactory bulb; 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）：我们小组的最新发现指向严重异常，影响精神分裂症受试者的内侧时间区域的细胞外基质（ECM），但没有双相情感障碍。我们的数据表明，在神经胶质细胞和ECM中，ECM的主要成分硫酸软骨蛋白蛋白聚糖（CSPGS）的异常表达。 CSPG在发育和吞噬过程中的功能，例如神经元迁移的调节，轴突出现，突触连通性的稳定，神经元网络的维持和神经元微环境，与精神分裂症的病理生理学直接相关。初步结果表明，患有Sz的受试者的嗅觉上皮（OE）和嗅球（OB）以及皮肤成纤维细胞中外周发生了类似的异常。如下所示，对嗅觉系统（OE和OB）中ECM异常的调查提供了令人信服的优势。首先，神经发育功能，例如神经元差异，OE中的迁移和轴突生长向OB出现，并与成人神经功能一起出现，使嗅觉系统非常适合于CSPGS进行研究。其次，越来越多的SZ嗅觉缺陷的证据，尤其是与负面症状有关的证据，使对嗅觉系统的研究与该疾病的临床表现直接相关。第三，OE是唯一可以通过活检轻松进入的中枢神经系统结构，可以从中开发出CEL培养物。这些研究的主要目的是研究精神分裂症中CSPG异常的病理生理与该疾病的临床表现之间的关系。 CSPG异常代表具有病理生理学相关性和精神分裂症特异性的生物学标志物的潜力，将在有关ECM异常机制的特定假设的背景下进行评估，及其与该疾病的核心症状相关。测试的主要假设是，由于调节CSPG合成的分子途径的破坏和Secrali0N的破坏，ECM异常会影响患有SZ受试者的嗅觉系统，并且可以在周围检测到。我们假设这种异常可能与特定的嗅觉缺陷和负面症状有关。为了检验这一假设，将从两个正常对照组的同类群体中评估OE和皮肤成纤维细胞（活检/体外）以及OB（后验尸）的CSPG异常。分别从皮肤和OE活检获得的人成纤维细胞和OE原发性培养物将用于测试，体外，诊断对调节CSPG表达的分子机制的影响。活检供体将接受嗅觉功能和精神病量表的测试。 BD受试者将被包括在内，以测试CSPG异常是SZ的特异性或代表主要精神病中的共同特征。