Molecular Basis of Iron Imbalance in sCJD Brain and CSF

sCJD 脑和脑脊液中铁失衡的分子基础

• 批准号: 8417651
• 负责人: Neena Singh
• 金额: $ 22.73万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-15 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8417651
• 关键词: Affect; Alzheimer' s Disease; Animal Model; Animals; Autopsy; Biological Markers; Blood; Blood Cells; Blood Circulation; Brain; Carrier Proteins; Cells; Cerebrospinal Fluid; Ceruloplasmin; Cessation of life; Chronic Wasting Disease; Creutzfeldt-Jakob Syndrome; Data; Dementia; Detection; Development; Diagnosis; Diagnostic; Diagnostic tests; Disease; Disease Progression; Evaluation; Ferritin; Goals; Grant; Hamsters; Homeostasis; Human; In Transferrin; Individual; Infection; Iron; Lumbar spinal cord structure; Modeling; Molecular; Monitor; Mus; Nature; Nerve Degeneration; Neurons; Oxidation-Reduction; Parkinson Disease; Pathogenesis; Pathology; Peripheral; Phenotype; PrPSc Proteins; Prion Diseases; Prions; Process; Prognostic Marker; Protein Isoforms; Proteins; Publishing; Radiolabeled; Regulation; Relative (related person); Risk; Sampling; Scrapie; Sensitivity and Specificity; Signal Transduction; Site; Tail; Testing; Time; Tissues; Transferrin; Transferrin Receptor; Veins; base; cervid; diagnostic accuracy; disease transmission; end stage disease; improved; iron deficiency; neurotoxicity; peripheral blood; prevent; prognostic; protein complex; radiotracer; response; therapeutic development; uptake

DESCRIPTION (provided by applicant): Sporadic Creutzfeldt-Jakob disease (sCJD) is a fatal prion disorder of humans that escapes detection until autopsy. The principal cause of neurotoxicity in this and other prion disorders is accumulation of PrP-scrapie (PrPSc), a ¿-sheet rich isoform of prion protein (PrPC) in the brain parenchyma. Participation of other processes is suspected, but their mechanism of action is unclear. Emerging evidence indicates that imbalance of iron homeostasis is a consistent feature of affected brains, implicating redox-iron in disease associated neurotoxicity. Unlike Alzheimer's disease (AD) where diseased brains accumulate iron, brains from sCJD and scrapie infected animal models reveal a phenotype of 'functional' iron deficiency as suggested by a significant increase in the iron uptake protein transferrin (Tf) despite minimal change in brain iron levels. Moreover, Tf levels increase with disease progression in direct correlation with PrPSc, suggesting a cause and effect relationship with disease pathogenesis. Surprisingly, instead of a compensatory increase, levels of Tf are significantly decreased in the cerebrospinal-fluid (CSF) of sCJD cases much before end-stage disease, indicating mis-regulation of signaling between iron starved brain parenchymal cells and the blood-brain and brain-CSF barriers involved in iron transport from the peripheral circulation to the brain and secretion of brain Tf respectively. Based on these observations, we hypothesize that sCJD associated disruption of brain iron regulation causes specific changes in CSF levels of iron management proteins that correlate with disease progression, providing disease specific biomarker(s) for sCJD. Two specific aims are proposed to test this hypothesis. In aim 1, the mechanism underlying decreased CSF Tf in sCJD brains will be explored using scrapie infected mice as models. Specifically, change in brain iron levels during scrapie infection, correlation between brain iron and PrPSc levels, and change in iron transport from the peripheral circulation to the brain will be monitored by tracking transport of radiolabeled iron (59Fe) from the tail vein to the brain and CSF compartments during prion disease progression. 59Fe counts in the brain and CSF will be correlated with levels of iron management proteins to evaluate the integrity of brain iron signaling mechanisms. In aim 2, the specificity and sensitivity of CSF Tf and other iron management proteins, the 'new' biomarkers, will be compared with 'current' surrogate CSF biomarkers of sCJD. The accuracy of new biomarkers in differentiating sCJD from rapidly progressive dementia and AD, potentially treatable causes of dementias often misdiagnosed as sCJD, will be emphasized. The prognostic reliability of new biomarkers will be assessed in CSF samples collected at different time points during disease progression from scrapie infected mice and Chronic Wasting Disease infected cervids, and the earliest time-point of a significant change will be identified. Successful completion of these studies will improve our understanding of the mechanism leading to decreased CSF Tf in sCJD, and facilitate the development of a rapid, specific, and sensitive pre-mortem diagnostic test for sCJD.

描述（由应用提供）：零星的克鲁特兹菲尔特 - 贾科布疾病（SCJD）是人类的致命儿童疾病，它逃避了检测直到尸检。在这种和其他prion疾病中神经毒性的主要原因是Prp -scrapie（PRPSC）的积累，这是脑实质中Prime蛋白（PRPC）富含同工型的eThele -sheet同工型。怀疑其他过程的参与，但它们的作用机理尚不清楚。新兴的证据表明，铁稳态失衡是受影响大脑的一致特征，暗示氧化还原与疾病相关的神经毒性。与阿尔茨海默氏病（AD）不同，解散的大脑会积聚铁，SCJD的大脑和被抓感染的动物模型揭示了尽管大脑铁水平的最小变化，但通过显着增加了铁摄取蛋白转移蛋白（TF）的表现。此外，与PRPSC直接相关的TF水平随疾病的进展而增加，这表明与疾病发病机理有因果关系和作用关系。令人惊讶的是，在末期疾病之前，SCJD病例的脑脊髓流体（CSF）的TF水平显着降低，而在终末期疾病发生之前，TF的水平显着降低，这表明铁饥饿的脑部吻合细胞与血液脑和脑CSF障碍物之间的信号传递不太调节来自脑部和脑部TF的脑周围循环中的铁障碍和脑CSF障碍所涉及。基于这些观察结果，我们假设SCJD相关的脑铁调节破坏会导致CSF水平管理蛋白水平的特定变化与疾病进展相关，从而为SCJD提供了特定于疾病的生物标志物。提出了两个具体目标来检验这一假设。在AIM 1中，将使用crapie感染的小鼠作为模型来探索SCJD大脑中CSF TF的基础机制。具体而言，将通过跟踪从尾静脉到脑静脉到脑部和CSF隔室期间，可以监测抓羊皮物感染期间脑铁水平的变化，脑铁与PRPSC水平之间的相关性以及从周围循环到大脑的铁转运的变化。大脑和CSF的59FE计数将与铁管理蛋白水平相关，以评估脑铁信号机制的完整性。在AIM 2中，将将CSF TF和其他铁管理蛋白（新的”生物标志物的特异性和敏感性与SCJD的“当前”替代CSF生物标志物进行比较。新生物标志物在将SCJD与迅速进行性痴呆和AD区分开的准确性（可能会被诊断为SCJD）的可能治疗的痴呆症原因和AD的准确性将被强调。新生物标志物的预后可靠性将在从crapie感染的小鼠和慢性浪费疾病感染的子宫颈的疾病进展过程中在不同时间点收集的CSF样本中进行评估，并确定最早的重大变化时间点。这些研究的成功完成将改善我们的 了解导致SCJD中CSF TF减少的机制，并支持SCJD快速，特定和敏感的验证前诊断测试的发展。