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: 6889930
• 负责人: Lars FREDRIK JARSKOG
• 金额: $ 16.73万
• 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/6889930
• 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疾病 其病因仍难以捉摸的疾病。无论是神经发育还是 神经退行性假说已被提出来解释其许多问题 临床和神经病理学特征。神经发育假说可以 解释了早期生命神经生物学之间观察到的关系 侮辱和成年后精神分裂症的发病率较高 残留的永久性大脑结构和功能缺陷。然而， 神经发育的观点可以解释许多主要的问题 特征包括症状休眠期延长 推定的侮辱和临床症状的出现，进行性 影响重要患者亚群的临床恶化，以及 最近的证据表明心室和心室进行性病理形态学变化 大脑皮层结构。根据这些数据，我们建议限制 神经退行性变可能与神经发育障碍同时发生，并且 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背后的机制。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 精神分裂症皮质。此外，初步数据表明存在关联 抗精神病治疗和较高的 Bcl-2 水平之间的关系。在一起，这些 研究结果为细胞凋亡调节蛋白的研究提供了理论依据 精神分裂症，无论是在病理生理学还是在治疗上 紊乱。 为了验证这一假设，我们对精神分裂症患者和对照组的死后脑组织进行了研究 将评估各组的 Bcl-2 和 caspase 家族蛋白。这些将是 通过 ELISA、免疫组织化学和蛋白质印迹进行测量。在平行大鼠中 模型中，新生大鼠将接受内毒素注射（一种模型） 感染）和 MK8O1（NMDA 功能减退模型）。急性和长期 将评估内毒素和 MK8O 1 对细胞凋亡、Bcl-2 家族的影响 人类死后组织中的蛋白质和半胱天冬酶。体视学 神经元细胞计数和体细胞大小的测量也将被评估。 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。

项目成果

microRNA expression in the prefrontal cortex of individuals with schizophrenia and schizoaffective disorder.

• DOI: 10.1186/gb-2007-8-2-r27
• 发表时间: 2007
• 期刊: Genome biology
• 影响因子: 12.3
• 作者: Perkins DO;Jeffries CD;Jarskog LF;Thomson JM;Woods K;Newman MA;Parker JS;Jin J;Hammond SM
• 通讯作者: Hammond SM

Developmental regulation of neural cell adhesion molecule in human prefrontal cortex.

• DOI: 10.1016/j.neuroscience.2009.04.037
• 发表时间: 2009-08-04
• 期刊: NEUROSCIENCE
• 影响因子: 3.3
• 作者: Cox, E. T.;Brennaman, L. H.;Gable, K. L.;Hamer, R. M.;Glantz, L. A.;Lamantia, A. -S.;Lieberman, J. A.;Gilmore, J. H.;Maness, P. F.;Jarskog, L. F.
• 通讯作者: Jarskog, L. F.