Extracellular anomalies in Schizophrenia: from molecules to symptoms

描述（由申请人提供）：我们小组的最新发现表明，精神分裂症受试者的内侧颞区细胞外基质（ECM）存在显著异常，但双相情感障碍受试者无此异常。我们的数据指出，异常表达的硫酸软骨素蛋白多糖（CSPGs），ECM的主要成分，在神经胶质细胞和ECM。CSPG在发育和成年期的功能，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有直接关系。初步结果表明，类似的异常发生在嗅上皮（OE）和嗅球（OB），以及外周皮肤成纤维细胞，与SZ的主题。调查ECM异常嗅觉系统（OE和OB），这里提出的，提供了令人信服的优势。首先，神经发育功能，如神经元分化，迁移在OE，轴突生长向OB，发生在整个生命中，伴随着成人的神经功能，使嗅觉系统非常适合调查CSPGs。第二，越来越多的证据表明，在深圳的嗅觉缺陷，特别是与阴性症状，使嗅觉系统的调查直接相关的临床表现，这种疾病。第三，OE是唯一的中枢神经系统结构，很容易通过活检，从细胞培养可以开发。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临床表现之间的关系。将在ECM异常机制及其与该疾病核心症状相关性的特定假设背景下，评估CSPG异常作为精神分裂症病理生理学相关性和特异性生物标志物的可能性。检验的主要假设是，由于调节CSPG合成和分泌的分子途径的破坏，ECM异常影响SZ受试者的嗅觉系统，并且可以在外周检测到。我们推测，这种异常可能与特定的嗅觉缺陷和阴性症状。为了检验这一假设，将在两个正常对照、SZ和BD受试者队列的OE和皮肤成纤维细胞（活检/体外）以及OB（尸检）中评估CSPG异常。分别从皮肤和OE活检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作用。活检供体将接受嗅觉功能和精神病评定量表的测试。将纳入BD受试者，以检测CSPG异常是否为SZ特有或代表重度精神病的共同特征。

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.