MRI contrast for molecular and cellular imaging of the brain

用于大脑分子和细胞成像的 MRI 对比

• 批准号: 10263037
• 负责人: Alan Koretsky
• 金额: $ 193.12万
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10263037
• 关键词: Adult; Anatomy; Animals; Brain; Brain imaging; Calcium; Calcium Channel; Cell physiology; Cells; Chelating Agents; Clinical; Collaborations; Contrast Media; Coupling; Data; Detection; Development; Dextrans; Disease; Disease model; Enzymes; Epilepsy; FDA approved; Formulation; Future; Gene Expression; Goals; Gold; Hemorrhage; Human; Image; Imaging Techniques; Immune; Injections; Intervention; Ions; Iron; Isotopes; Label; Ligands; Magnetic Resonance Imaging; Manganese; Manuscripts; Measures; Metals; Microfabrication; Midbrain structure; Modeling; Modernization; Molecular; Molecular Weight; Monitor; Motor Pathways; Neurons; Nose; Odors; Olfactory Pathways; Particle Size; Patients; Pattern; Perfusion; Phase; Physiological; Pituitary Gland; Polymers; Positron; Positron-Emission Tomography; Pre-Clinical Model; Process; Property; Protocols documentation; Publishing; Rattus; Recovery; Reporter; Reporting; Rodent; Structure; Synapses; T-Lymphocyte; Techniques; Testing; Tissues; Tracer; Translating; Translations; Transplantation; Tumor-infiltrating immune cells; United States National Institutes of Health; Viral; Virus Diseases; Wireless Technology; Work; base; blood-brain barrier disruption; brain parenchyma; brain tissue; cell motility; cellular imaging; detector; human imaging; imaging approach; improved; in vivo; interest; iron oxide; migration; molecular imaging; mouse model; multiple sclerosis patient; nerve stem cell; neural circuit; novel; olfactory bulb; particle; preclinical imaging; precursor cell; radiological imaging; receptor; relating to nervous system; sensor; subventricular zone; success; voltage; volunteer

There continues to be increasing interest in developing molecular imaging approaches that enable traditional radiological imaging techniques to obtain a wide range of information about molecular and cellular processes. A range of information is considered important such as the ability to monitor cell migration, the development of reporters that enable imaging of gene expression, the development of robust strategies to image receptors, and the development of environmentally sensitive agents that can be used to detect the presence of specific enzymes or monitor changes in ion status. The long term goals of this work are to develop strategies that enable MRI contrast that is sensitive to a wide range of molecular and cellular processes. This work builds on over 30 years of work where we have demonstrated the first MRI strategy for detecting gene expression, the first MRI approach for monitoring a surrogate of calcium influx, the first MRI approach for performing neuronal track tracing, and the first MRI approach for monitoring the migration of single cells in vivo. These all represented initial reports by any radiological imaging technique which enabled these processes to be measured and are finding widespread application to imaging pre-clinical models disease. We have made progress in the specific aims. Aim 1: Develop iron oxide based contrast for labeling and imaging the migration of endogenous neural stem cells. Over the past few years we have demonstrated the unique advantages of micron sized iron oxide particles for MRI of specific cells. Single cells can be detected and indeed, single particles within single cells can be detected. The main paradigm for MRI of cell migration is to label cells ex vivo and monitor migration after transplantation into an animal. The ability to detect a single particle enables inefficient labeling strategies. In particular, over the past few years we have demonstrated that injection of particles into the ventricles of the rat brain enables particles to be taken up by neural precursors in the sub-ventricular zone and MRI can monitor the migration of cells to the olfactory bulb. Previously, we have measured the changes in migration of new neurons during unilateral nasal occlusion and recovery showing that the was exquisite coupling between bulb anatomy and cell migration both during nasal block and recovery. Studies to determine whether introduction of specific odors after naris occlusion alters the pattern of migration of the cells into the bulb have been delayed due to improvements in cell labeling (Aim 2). In a new project inspired by studying these endogenous new neurons we have shown that cortical and mid-brain precursor cells can be grown in the adult CSF to form fully integrated and normally appearing brain tissue. Over the past year we have almost completed studies that show this new tissue can integrate into the motor pathway and olfactory pathways if placed in appropriate places in the CSF. These studies shave led to us to return to making MRI neural circuit tracers and we have increased our ability to detect a classical tracer, CTB by about five fold (Aim 4). This new tracer should allow us to determine how the tissue in CSF connect to the host brain. A second major project images the entire brain to study immune brain interactions. We are close to completing studies to detect T cell migration into the brain at single cell level during virus infection in mouse models. Interesting T cell accumulation is associated with small bleeding opening the issue of whether T cell infiltration into brain parenchyma is associated with BBB breakdown in these viral models even when very few cells are involved. Aim 2: Apply microfabrication techniques to manufacture unique metal structures that may be valuable for MRI contrast. Iron oxide particles commonly used for MRI are very potent contrast agents enabling detection of single micron sized particles. However, due to bulk phase manufacture of particles they are not very uniform and they do not contain very high content of metal. A solution to this problem is to use modern microfabrication techniques to manufacture metal based, micron sized contrast agents. Over the past few years we have shown that double doughnut, cylinders, and ellipsoid structures offer unique advantages for distinguishing particles and that these structures can be turned into sensors for pH. Over the past year we are completing a study that demonstrates that simple microfabricated gold coated iron discs can be used for both our new neuron and immune cell tracking projects. Finally, our collaborator at NIST, Gary Zabow (former fellow)has developed novel ways to manufacture this class of MRI contrast that are being tested here at NIH. Finally, over the past couple of years, in collaboration with M. Barbic, we have demonstrated that magnetocaloric materials have unique properties that have potential to be very useful for MRI studies of cell tracking. these proof of principle studies set the stage for future work attempting to make these materials in small particle formulations. Aim 3: Develop novel delivery mechanisms to extend the applicability of manganese enhanced MRI. Over the past ten years we have demonstrated the remarkable utility of the manganese ion for MRI contrast. Manganese ion enters cells on ligand or voltage gated calcium channels and so can be used as an MRI agent to monitor calcium influx. Once inside of neurons, manganese will move in an anterograde direction and cross functional synapses enabling neuronal networks to be imaged with MRI. Finally, manganese given systemically gives cytoarchitectural information about the rodent brain. These successes have us interested in broadening the ways in which manganese ion can be delivered to cells. A major limitation of manganese enhanced MRI are the concentrations required. This limits translation for use in human imaging. Over the past couple of years we have tackled this problem in two ways, we have published an initial study that demonstrates that manganese positron emitting isotopes will enable PET to obtain similar information that can be obtained with manganese enhanced MRI, including neural tracing and functional activation of tissue. Discussion have begun to decide if to translate this to human studies. We completed our first study in collaboration with Daniel Reich to test if an FDA approved agent that releases Mn might be useful for disease detection. The first manuscript on normal volunteers was published. Studies on MS patients were completed this past year and studies of patients with epilepsy are underway in collaboration with Sara Inati. Please note all human studies are done under the protocols of our collaborators and that is where the relevant human use data is reported for this work. Aim 4: Develop strategies that enable cellular processes to alter the relaxivity of MRI contrast agents. We continue to develop the microfabricated particles produced under Aim 2 as sensors. Over the past few years we have completed a study that demonstrates that the microfabricated particles can be made into a sensors. Over the past year we have sought ways to make the manufacture of this very interesting class of sensors more robust. In addition, we have developed a novel polymer of Gd chelates that has high relaxivity but relatively low molecular weight. This has been attached to a class of classical neural tracers (CTB and dextrans) to enable MRI neural tracers. This platform should enable us to make new classes of physiologically responsive MRI agents. When opportunities arise we make specialized MRI detectors for specific projects This includes an interventional pituitary coil that is being tested by Dr. Chittiboina, a coil for improving perfusion MRI, and approaches to make wireless detectors.

人们对开发分子成像方法越来越感兴趣，这些方法使传统的放射成像技术能够获得有关分子和细胞过程的广泛信息。 一系列信息被认为是重要的，例如监测细胞迁移的能力、能够对基因表达进行成像的报告基因的开发、对受体成像的稳健策略的开发以及可用于检测细胞迁移的环境敏感剂的开发。特定酶的存在或监测离子状态的变化。 这项工作的长期目标是开发策略，使 MRI 对比对广泛的分子和细胞过程敏感。 这项工作建立在 30 多年的工作基础上，我们已经展示了第一个用于检测基因表达的 MRI 策略、第一个用于监测钙流入替代物的 MRI 方法、第一个用于执行神经元轨迹追踪的 MRI 方法以及第一个用于监测体内单细胞的迁移。 这些都代表了任何放射成像技术的初步报告，这些技术使得这些过程能够被测量，并且正在广泛应用于临床前模型疾病的成像。 我们在具体目标上取得了进展。 目标 1：开发基于氧化铁的造影剂，用于标记内源性神经干细胞的迁移并对其进行成像。 在过去的几年中，我们已经展示了微米级氧化铁颗粒用于特定细胞 MRI 的独特优势。 可以检测单个细胞，并且实际上可以检测单个细胞内的单个颗粒。 细胞迁移 MRI 的主要范例是离体标记细胞并监测移植到动物体内后的迁移。检测单个粒子的能力使得标记策略效率低下。特别是，在过去的几年里，我们已经证明，将颗粒注射到大鼠脑室中，可以使颗粒被脑室下区的神经前体细胞吸收，并且 MRI 可以监测细胞向嗅球的迁移。 之前，我们测量了单侧鼻阻塞和恢复过程中新神经元迁移的变化，表明鼻阻塞和恢复过程中球解剖结构和细胞迁移之间存在微妙的耦合。由于细胞标记的改进，确定鼻孔阻塞后引入特定气味是否会改变细胞迁移到球部的模式的研究已被推迟（目标 2）。在一个受研究这些内源性新神经元启发的新项目中，我们发现皮质和中脑前体细胞可以在成人脑脊液中生长，形成完全整合且外观正常的脑组织。在过去的一年里，我们几乎完成了研究，表明如果将这种新组织放置在脑脊液中的适当位置，它可以整合到运动通路和嗅觉通路中。 这些研究促使我们重新开始制造 MRI 神经回路示踪剂，并且我们将检测经典示踪剂 CTB 的能力提高了约五倍（目标 4）。 这种新的示踪剂应该能让我们确定脑脊液中的组织如何与宿主大脑连接。 第二个主要项目对整个大脑进行成像，以研究免疫大脑相互作用。我们即将完成在小鼠模型中检测病毒感染期间 T 细胞在单细胞水平上迁移到大脑的研究。有趣的 T 细胞积聚与小出血有关，这开启了 T 细胞浸润脑实质是否与这些病毒模型中的 BBB 破坏相关的问题，即使涉及的细胞很少。 目标 2：应用微加工技术来制造可能对 MRI 对比有价值的独特金属结构。 常用于 MRI 的氧化铁颗粒是非常有效的造影剂，能够检测单微米大小的颗粒。 然而，由于颗粒的本体相制造，它们不是很均匀，并且它们不包含非常高含量的金属。 该问题的解决方案是使用现代微加工技术来制造基于金属的微米级造影剂。 在过去的几年里，我们已经证明，双环形、圆柱体和椭圆体结构为区分颗粒提供了独特的优势，并且这些结构可以转变为 pH 传感器。在过去的一年里，我们正在完成一项研究，该研究表明简单的微加工镀金铁盘可用于我们的新神经元和免疫细胞跟踪项目。最后，我们在 NIST 的合作者 Gary Zabow（前研究员）开发了制造此类 MRI 造影剂的新方法，并正在 NIH 进行测试。最后，在过去几年中，我们与 M. Barbic 合作，证明了磁热材料具有独特的特性，有可能对细胞跟踪的 MRI 研究非常有用。 这些原理证明研究为未来尝试以小颗粒配方制造这些材料的工作奠定了基础。 目标 3：开发新的传递机制以扩展锰增强 MRI 的适用性。 在过去的十年中，我们已经证明了锰离子在 MRI 对比方面的显着效用。 锰离子通过配体或电压门控钙通道进入细胞，因此可用作 MRI 试剂来监测钙流入。 一旦进入神经元内部，锰将沿顺行方向移动并跨功能突触，使神经元网络能够通过 MRI 进行成像。 最后，系统地给予锰可以提供有关啮齿动物大脑的细胞结构信息。 这些成功使我们对拓宽将锰离子输送到细胞的方式感兴趣。锰增强 MRI 的一个主要限制是所需的浓度。这限制了翻译在人类成像中的使用。 在过去的几年里，我们通过两种方式解决了这个问题，我们发表了一项初步研究，表明锰正电子发射同位素将使 PET 能够获得与锰增强 MRI 类似的信息，包括神经追踪和功能激活组织。已经开始讨论决定是否将其转化为人类研究。 我们与 Daniel Reich 合作完成了第一项研究，以测试 FDA 批准的释放锰的药物是否可用于疾病检测。第一篇关于普通志愿者的手稿出版。对多发性硬化症患者的研究已于去年完成，目前与 Sara Inati 合作正在进行对癫痫患者的研究。请注意，所有人类研究都是根据我们合作者的协议进行的，这就是本工作报告的相关人类使用数据的地方。 目标 4：制定策略，使细胞过程能够改变 MRI 造影剂的弛豫度。 我们继续开发 Aim 2 下生产的微加工颗粒作为传感器。 在过去的几年里，我们完成了一项研究，证明微加工颗粒可以制成传感器。在过去的一年里，我们一直在寻找方法，使这种非常有趣的传感器的制造更加稳健。此外，我们还开发了一种新型的 Gd 螯合物聚合物，它具有高弛豫率但分子量相对较低。它已附加到一类经典神经示踪剂（CTB 和葡聚糖）上，以实现 MRI 神经示踪剂。这个平台应该使我们能够制造新型的生理响应 MRI 试剂。 当机会出现时，我们会为特定项目制造专门的 MRI 探测器，其中包括 Chittiboina 博士正在测试的介入性垂体线圈、用于改善灌注 MRI 的线圈以及制造无线探测器的方法。