Understanding hippocampal internal architecture in human temporal lobe epilepsy -- from MRI to epigenetics

了解人类颞叶癫痫的海马内部结构——从 MRI 到表观遗传学

• 批准号: 9318610
• 负责人: Lawrence Ver Hoef
• 金额: $ 53.76万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9318610
• 关键词: Address; Adult; Age of Onset; Architecture; Astrocytes; Attention; Autologous; Autopsy; Behavior; Benchmarking; Biochemical Markers; Biological Markers; Brain; Clinical; DNA; DNA Methylation; Data; Detection; Diagnosis; Diagnostic radiologic examination; Disease; Drug resistance; Enrollment; Epigenetic Process; Epilepsy; Evaluation; Excision; Frequencies; Gene Expression Profiling; Gene Proteins; Gene Targeting; Genes; Genetic; Genetic Transcription; Glial Fibrillary Acidic Protein; Gliosis; Goals; Grant; Health; Hippocampus (Brain); Human; Image; Imagery; Imaging Techniques; Individual; Intractable Epilepsy; Lateral; Literature; MRI Scans; Magnetic Resonance Imaging; Measures; Medical; Methods; Methylation; Microscope; Microscopic; Microscopy; Modality; Modeling; Modification; National Institute of Biomedical Imaging and Bioengineering; National Institute of Neurological Disorders and Stroke; Operative Surgical Procedures; Pathologic; Pathology; Patients; Pattern; Performance; Phase; Play; Process; Protein Biosynthesis; Recruitment Activity; Refractory; Research; Resected; Resolution; Role; Scanning; Seizures; Series; Signal Pathway; Signal Transduction; Site; Specialist; Specimen; Structure; Syndrome; Techniques; Temporal Lobe Epilepsy; Testing; Tissues; Universities; Work; astrogliosis; base; career development; case control; cell type; gray matter; high resolution imaging; hippocampal atrophy; hippocampal sclerosis; human tissue; improved; internal control; neuroimaging; neuron loss; new therapeutic target; novel; predictive marker; predictive of treatment response; promoter; protein expression; response; secondary analysis; tool; transcriptomics; white matter

Project Summary/Abstract This project centers around the hippocampus, a part of the brain where seizures frequently occur in the most common form of epilepsy in adults, temporal lobe epilepsy. Through a career development grant I have had over the last five years through the National Institute of Biomedical Imaging and Bioengineering I have developed a technique called HR-MICRA that produces exceptionally high-resolution MRI images. This is meaningful for the study of epilepsy because the hippocampus is not only the most epileptogenic structure in the brain but it also has an extremely complicated internal architecture that is difficult to visualize with conventional MRI techniques. Our preliminary data shows that the HR-MICRA technique is far superior to conventional MRI techniques in regard to visualizing the internal structure of the hippocampus clearly and consistently. Our preliminary data also shows that subtle abnormalities of the internal structure of the hippocampus occur more frequently than previously thought even when the hippocampus overall looks relatively normal. In this project we will compare the HR-MICRA technique on a regular 3T MRI scanner to an equivalent technique using a powerful 7T research scanner at Auburn University, which there are only a few of in the nation. If we show that 3T HR-MICRA is equivalent to 7T imaging, it will provide a tool to epilepsy specialist and neuroscientists that can be relatively easily implement on most clinical scanners. In the second part of this project we will use these high-resolution imaging techniques to study the internal structure of the hippocamps in two groups of epilepsy patients -- those whose seizures are well-controlled and those whose seizures are poorly controlled. We hypothesize that the high-resolution technique will show a subtle but definite degree of blurring of the layers in the internal structure of the hippocampus that is more prominent in patients with poorly controlled seizures. We then hypothesize that this blurring is due to activation of certain types of cells in the brain called astrocytes. We will test this by scanning a series of patients with poorly controlled seizures who then subsequently go on to have surgery to remove the hippocampus that is causing their seizures. We will then examine their resected hippocampi under the microscope and assess whether there is an increased degree of astrogliosis (more activated astrocytes) in certain layers, which would make certain layers harder to see on the MRI scan. In the last phase of the project we will determine whether epigenetic modification of the astrocytes' DNA is playing a role. Epigenetic modification refers to a natural process whereby certain genes are turned on or off. If we do find that epigenetic mechanisms are at play in temporal lobe epilepsy it may provide new therapeutic targets and advance our understanding of how the brain works in disease and in health.

项目总结/摘要 这个项目围绕海马体，大脑的一部分，癫痫发作经常发生在最 成人癫痫的常见形式，颞叶癫痫。通过职业发展补助金， 在过去的五年里，通过国家生物医学成像和生物工程研究所， 开发了一种名为HR-MICRA的技术，可以产生非常高分辨率的MRI图像。这是 这对于癫痫的研究是有意义的，因为海马不仅是大脑中最易致癫痫的结构， 但它也有一个非常复杂的内部结构，很难想象， 常规MRI技术。我们的初步数据表明，HR-MICRA技术远优于上级 常规MRI技术在清晰地可视化海马体的内部结构方面， 始终如一我们的初步数据还表明， 海马体出现的频率比以前认为的更高，即使海马体整体看起来 相对正常。在这个项目中，我们将比较HR-MICRA技术在一个普通的3 T MRI扫描仪， 在奥本大学使用强大的7 T研究扫描仪，这是一种相当的技术， 在全国范围内。如果我们证明3 T HR-MICRA与7 T成像相当，它将为癫痫提供一种工具 这可以相对容易地在大多数临床扫描仪上实现。在第二 作为该项目的一部分，我们将使用这些高分辨率成像技术来研究 在两组癫痫患者中进行了药物治疗--那些癫痫发作得到良好控制的患者和那些 癫痫控制得很差。我们假设高分辨率技术将显示一个微妙但明确的 海马体内部结构中各层的模糊程度，在患者中更为突出 癫痫控制不佳然后，我们假设这种模糊是由于某些类型的激活， 大脑中的一种叫做星形胶质细胞的细胞。我们将通过扫描一系列控制不良的患者来测试这一点。 癫痫患者随后进行手术，切除导致癫痫发作的海马体。 癫痫发作。然后，我们将在显微镜下检查他们切除的隆突，并评估是否有 某些层中星形胶质细胞增生程度增加（更多活化的星形胶质细胞），这将使某些 在核磁共振扫描中很难看到的层。在项目的最后阶段，我们将确定表观遗传是否 星形胶质细胞DNA的修饰起了作用。表观遗传修饰是指一种自然过程 从而开启或关闭某些基因。如果我们真的发现表观遗传机制在时间上起作用， 它可能提供新的治疗靶点，并促进我们对大脑如何工作的理解。 疾病和健康。