Bcl-2 Family Protein and Apoptosis in Schizophrenia

精神分裂症中的 Bcl-2 家族蛋白和细胞凋亡

• 批准号: 6740768
• 负责人: Lars FREDRIK JARSKOG
• 金额: $ 16.4万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6740768
• 关键词: BCL2 gene /protein; apoptosis; cysteine endopeptidases; developmental neurobiology; dizocilpine; enzyme linked immunosorbent assay; gene expression; human tissue; immunocytochemistry; laboratory rat; schizophrenia; transcription factor; western blottings

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.

描述：（由申请人提供）Zepiria是一种复杂的神经精神病 病因学仍不清楚的疾病。神经发育和 已经提出了神经退行性假说来解释其许多 临床和神经病理学特征。神经发育假说可以 解释了观察到的早期生命神经生物学 侮辱和成年期精神分裂症的发病率较高， 残留的永久性脑结构和功能缺陷但 神经发育的观点福尔斯下降到解释一些主要的 特征包括症状休眠期的延长， 假定的侮辱和临床症状的出现，进行性 影响重要患者亚组的临床恶化， 最近的证据表明，在心室和 大脑皮层结构根据这些数据，我们建议， 神经变性可与神经发育障碍同时发生， 凋亡调节蛋白的失调是一个理想的候选者 这两个看似不同的过程背后的机制。的 本研究假设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Bcl-2蛋白在死后下调， 精神分裂症皮层此外，初步数据表明， 抗精神病药物治疗和高Bcl-2水平之间的联系所有这些 这些发现为研究细胞凋亡调控蛋白提供了理论基础， 精神分裂症，无论是在病理生理学和治疗这一点， disorder. 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 将评估各组的Bcl-2和胱天蛋白酶家族蛋白。这些将是 通过ELISA、免疫组织化学和蛋白质印迹来测量。在平行大鼠中， 模型中，新生大鼠将接受内毒素注射（内毒素模型）。 感染）和MK 801（NMDA功能减退模型）。急性和长期 将评估内毒素和MK 80 1对细胞凋亡、Bcl-2家族 蛋白质和半胱天冬酶，就像人类死后的组织一样。立体学 还将评估神经元细胞计数和体大小的测量。 最后，年轻的成年大鼠将接受典型和非典型抗精神病药物， 评估它们对凋亡调节蛋白的影响。