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: 6334138
• 负责人: Lars FREDRIK JARSKOG
• 金额: $ 15.23万
• 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/6334138
• 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）Zophrenia是一种复杂的神经精神病学 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设来解释其许多 临床和神经病理学特征。神经发育假设可以 解释了早期神经生物学之间观察到的关系 侮辱和成年后的精神分裂症发病率更高 残留的永久性结构和功能性脑缺陷。但是， 神经发育的视角降低了许多红衣主教 功能包括旷日持久的症状休眠期 推定的侮辱和临床症状的出现 影响大量患者亚组的临床恶化， 最新证据表明心室和心室和 皮质大脑结构。鉴于这些数据，我们建议有限 神经变性可能与神经发育障碍一起发生 凋亡调节蛋白的失调是理想的候选者 这两个看似不同的过程的基础的机制。这 这项研究的假设是凋亡调节蛋白有助于 精神分裂症的基本病理生理学。候选人有证据 神经保护性Bcl-2蛋白在验尸中下调 精神分裂性皮质。此外，初步数据表明关联 在抗精神病药物治疗和较高的Bcl-2水平之间。在一起，这些 发现为研究凋亡调节蛋白的研究提供了理由 精神分裂症，无论是在病理生理学还是在治疗中 紊乱。 为了检验该假设，来自精神分裂症和对照的死后脑组织 将对BCL-2和caspase家族蛋白进行评估组。这些将是 通过ELISA，免疫组织化学和蛋白质印迹测量。在平行大鼠中 模型，新生大鼠将收到内托氧气的注射（一种模型 感染）和MK8O1（NMDA功能障碍的模型）。急性和长期 将评估内托Xrn和Mk8o 1的效果，以凋亡，Bcl-2家族 蛋白质和胱天蛋白酶与人类后组织一样。立体论 还将评估神经元细胞的计数和摩尔大小的测量。 最后，年轻的成年大鼠将获得典型和非典型的抗精神病药 评估它们对凋亡调节蛋白的影响。