Bcl-2 Family Protein and Apoptosis in Schizophrenia

描述：(申请人提供)精神分裂症是一种复杂的神经精神疾病 病因仍然难以捉摸的疾病。神经发育和 已经提出了神经退行性假说来解释它的许多 临床和神经病理特点。神经发育假说可以 解释观察到的早期生命与神经生物学之间的关系 侮辱与成年后精神分裂症的高发病率 残留的永久性结构性和功能性脑缺陷。然而， 神经发育的观点可以解释许多基本的 特征包括长时间的症状休眠期 推定的侮辱和出现的临床症状，进行性 影响到相当一部分患者的临床恶化，以及 最近有证据表明，脑室和脑室的进行性病理形态改变 大脑皮层结构。根据这些数据，我们认为有限的 神经退行性变可能与神经发育障碍同时发生 细胞凋亡调节蛋白的失调是一个理想的候选者 作为这两个看似不同的过程的基础的机制。这个 这项研究的假设是，凋亡调节蛋白有助于 精神分裂症的潜在病理生理学。候选人有证据 神经保护性的Bcl2蛋白在死后下调 精神分裂症皮质。此外，初步数据表明， 抗精神病药物治疗和较高的Bc l-2水平之间的关系。加在一起，这些 这些发现为研究细胞凋亡调节蛋白提供了理论基础。 精神分裂症，在病理生理学和治疗上都是如此 无序。 为了验证这一假设，精神分裂症患者和对照组的死后脑组织 将对各组进行Bcl-2和caspase家族蛋白的评估。这些将是 采用ELISA法、免疫组织化学法和Western blotts法进行检测。在平行鼠中 模型，新生大鼠将接受内毒素注射(一种模型 感染)和MK8O1(NMDA功能低下的模型)。急慢性和长期性 将评估内毒素和MK8O 1对细胞凋亡的影响，Bcl-2家族 蛋白质和半胱氨酸酶，就像在人类死后组织中一样。体视学 还将评估神经细胞计数和胞体大小的测量。 最后，年轻的成年大鼠将接受典型和非典型的抗精神病药物 评估它们对细胞凋亡调节蛋白的影响。

DESCRIPTION: (provided by applicant) Zophrenia is a complex neuropsychiatric disorder whose etiology has remained elusive. Both neurodevelopmental and neurodegenerative hypotheses have been proposed to account for its many clinical and neuropathological features. The neurodevelopmental hypothesis can account for the observed relationship between early life neurobiological insults and a higher incidence of schizophrenia in adulthood with associated residual permanent structural and functional brain deficits. However, the neurodevelopmental perspective falls to account for a number of cardinal features including the protracted period of symptomatic dormancy between the putative insult and the emergence of clinical symptoms, the progressive clinical deterioration that affects a significant subgroup of patients, and the recent evidence for progressive pathomorphological changes in ventricular and cortical brain structures. In light of these data, we suggest that limited neurodegeneration may occur in concert with a neurodevelopmental disorder and that a dysregulation of apoptotic regulatory proteins is an ideal candidate mechanism to underlie both of these seemingly divergent processes. The hypothesis of this study is that apoptotic regulatory proteins contribute to the underlying pathophysiology of schizophrenia. The candidate has evidence that the neuroprotective Bcl-2 protein is downregulated in postmortem schizophrenic cortex. Furthermore, preliminary data suggest an association between antipsychotic treatment and higher Bcl-2 levels. Together, these findings provide a rationale for the study of apoptotic regulatory proteins in schizophrenia, both in the pathophysiology and in the treatment of this disorder. To test this hypothesis, postmortem brain tissue from schizophrenic and control groups will be assessed for Bcl-2 and caspase family proteins. These will be measured by ELISA, immunohistochemistry and Western blots. In a parallel rat model, neonatal rats will receive injections of endotoxrn (a model of infection) and MK8O1 (a model of NMDA hypofunction). Acute and long-term effects of endotoxrn and MK8O 1 will be assessed for apoptosis, Bcl-2 family proteins, and caspases as in the human post-mortem tissue. Stereological neuronal cell counting and measurement of somal size will also be assessed. Finally, young adult rats will receive typical and atypical antipsychotics to assess their effect on the apoptotic regulatory proteins.