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Genetically-controlled MRI contrast agents for functional brain imaging

用于功能性脑成像的基因控制 MRI 造影剂

基本信息

批准号：
7430130
负责人：
Alan Jasanoff
金额：
$ 251.75万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-30 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7430130
关键词：
A 101 A549 Address Adenosine Adenovirus Vector Adopted Adverse effects Affect Affinity Aftercare Amygdaloid structure Animals Antibodies Ants Anus Area Ascorbic Acid Atomic Force Microscopy Attenuated Award Behavior Behavioral Behavioral Paradigm Binding Biochemical Biochemistry Biological Biological Assay Biological Sciences Biology Biophysics Biosensor Blood Blood - brain barrier anatomy Blood Vessels Blood flow Bovine Serum Albumin Brain Brain imaging Breathing Buffers Calcium Calmodulin Carbon Dioxide Carbonic Anhydrase Inhibitors Cations Cell Culture System Cell Line Cell Nucleus Cell surface Cells Cerebrum Charge Chelating Agents Chemical Engineering Chemicals Chemistry Chimeric Proteins Chromosome Pairing Cisplatin/Doxorubicin/Melphalan/Teniposide Class Cleaved cell Code Cognitive Collaborations Color Communities Compatible Condition Conservatism Contrast Media Cortical Column Coupled Coupling Creativeness Cultured Cells Cytokinins DNA Binding Data Data Set Decision Making Depressed mood Depth Detection Development Diffusion Discipline Disruption Dreams Eating Edetic Acid Electrical Engineering Electrodes Electrophysiology (science)Elements Engineering Ensure Environmental Risk Factor Enzyme Gene Enzymes Event Evolution FOS gene Ferritin Fluorescence Fluorescence Microscopy Fluorescence-Activated Cell Sorting Foundations Functional Imaging Functional Magnetic Resonance Imaging Funding Gene Expression Generations Generic Drugs Genes Genetic Genetic Transcription Goals Gold Grant Green Fluorescent Proteins Health Hemoglobin Herpesviridae Hip region structure Hippocampus (Brain)Histocytochemistry Hour Housing Human Hydrolysis Image Imaging technology Immediate-Early Genes Immunohistochemistry Implanted Electrodes In Situ Hybridization In Vitro Individual Infection Information Systems Injection of therapeutic agent Inosine Institutes Intracellular Second Messenger Investigation Ionomycin Ionophores Iron Kinetics Knowledge Label Laboratories LacZ Genes Lactamase Lead Learning Left Length Life Light Location Magnetic Resonance Magnetic Resonance Imaging Magnetism Maize Mammalian Cell Manganese Maps Mathematics Measurement Measures Mechanics Mediating Memory Mentorship Metabolism Methods Microscopy Mining Mission Modeling Molecular Molecular Biology Monitor Monkeys Mus Mutagenesis Mutation Nature Nerve Degeneration Nervous system structure Neurobiology Neuronal Plasticity Neurons Neurophysiology - biologic function Neurosciences Neurosciences Research Neurotransmitter Receptor Neurotransmitters New Territories New York Noise Nuclear Nucleic Acid Probes Nucleic Acids Nucleotides Numbers Odorant Receptors Optics Organism Output Oxidases Oxygen Paper Paralysed Particle Size Pathway interactions Pattern Penicillins Peptides Perception Performance Phosphate Buffer Phosphopeptides Phosphotransferases Physics Physiologic pulse Physiological Physiology Plants Population Positioning Attribute Postdoctoral Fellow Preparation Prion Diseases Problem Solving Procedures Process Protein Engineering Protein Overexpression Proteins Protocols documentation Prussian blue Publications Publishing Pulse taking Qualifying Range Rate Rattus Reading Reagent Recovery Reducing Agents Relative (related person)Relaxation Reporter Reporting Research Research Infrastructure Research Personnel Research Project Grants Resolution Rest Risk Risk-Taking Rodent Role S-1 Antimetabolite agent SNAP receptor Saline Sampling Scanning Scheme Schools Science Scientist Screening procedure Second Messenger Systems Sensory Series Shoulder Signal Transduction Signal Transduction Pathway Simplexvirus Site Site-Directed Mutagenesis Slice Solubility Solutions Somatosensory Cortex Spatial Distribution Specificity Speed Staging Staining method Stains Standards of Weights and Measures Stimulus Structure Students Subfamily lentivirinae Supplementation Surface Synapses Synaptic Transmission Synaptic Vesicles System Technical Expertise Techniques Technology Tertiary Protein Structure Testing Time Tissues Today Toxic effect Training Transfection Transferrin Transferrin Receptor Transgenes Transgenic Animals Transgenic Mice United States National Institutes of Health Universities Validation Variant Vasodilator Agents Vesicle Viral Viral Vector Virus Water Weight Work Writing abstracting adenosine deaminase adenoviral-mediated analog antisense nucleic acid aptamer awake base beta-Lactamase blood oxygen level dependent brain research career cell growth cell type computer science conditioning crosslink day defective adenoviral vector design enzyme substrate experience falls fly forging gel electrophoresis genetic manipulation hemodynamics high throughput screening human VAPA protein improved in vivo interest interstitial iron oxide light scattering luminescence magnetite ferrosoferric oxide method development mind control model design molecular imaging monomer mouse model multidisciplinary mutant nanoparticle neural circuit neural stimulation neuroimaging neuromechanism neurophysiology neuroregulation neurotechnology neurotoxic new technology next generation novel olfactory bulb optical imaging particle postnatal pressure programs promoter protein aggregate protein metabolite prototype quantum receptor expression relating to nervous system research study response second messenger selective expression sensor sensory cortex size small molecule somatosensory structural biology subcutaneous success synthetic peptide theories transgene expression trend vector vesicular SNARE proteins willingness

项目摘要

Understanding how the brain controls behavior is one of the outstanding scientific problems of today. The methods most needed to study neural mechanisms of behavior will combine the noninvasiveness and whole-brain coverage of magnetic resonance imaging (MRI) with the precision of cellular recording tech- niques like electrophysiology and fluorescence microscopy. Here we propose to develop a new set of neu- roimaging techniques that approach this ideal. The methods rely on the use of protein-based sensors that report aspects of neural function and may be targeted to specific cells or cell types. Unlike protein sensors developed previously for optical imaging, the sensors we propose to create will incorporate MRI contrast agents, meaning that they can be monitored across entire, intact brains; genetic targeting will allow neural activity of defined “circuit elements” to be identified and integrated into explanatory models of brain function. In the first two Specific Aims, we propose to form and apply genetically-encoded calcium-sensitive contrast agents based on the iron storage protein ferritin (Ft). Our preliminary data and recently published results indicate feasibility of the design, which we will test in rats once it has been validated in cell culture. Ft- based sensors may not offer enough sensitivity for functional imaging of sparse or subtle changes in neu- ronal physiology, however. To address this, we propose in Aims 3-4 to develop a second genetically- controlled system in which markers of neuronal activity are transduced and amplified by enzymes into ro- bust signals that may be read out using powerful exogenous contrast agents. This program is an ambitious and high-impact endeavor that, once accomplished, will change the way researchers study the brain. The PI and his laboratory have the diversity of experience, record of effective collaborations, and risk-taking spirit that will allow them to introduce a new generation of brain measurements and empirical approaches in neuroscience.

了解大脑如何控制行为是当今突出的科学问题之一。研究行为的神经机制最需要的方法将联合收割机的非侵入性和磁共振成像（MRI）的全脑覆盖，具有细胞记录技术的精度，比如电生理学和荧光显微镜。在这里，我们建议开发一套新的新- 这是一种接近这一理想的图像处理技术。这些方法依赖于使用基于蛋白质的传感器，报告神经功能的各个方面，并且可以靶向特定的细胞或细胞类型。与蛋白质传感器不同我们之前为光学成像开发的传感器，我们提议创建的传感器将包含MRI对比度这意味着它们可以在整个完整的大脑中进行监测;遗传靶向将允许神经活动的定义“电路元件”被识别和整合到解释模型的大脑功能。在前两个具体目标中，我们建议形成和应用遗传编码的钙敏感对比基于铁储存蛋白铁蛋白（Ft）的药物。我们的初步数据和最近发表的结果表明设计的可行性，一旦在细胞培养中得到验证，我们将在大鼠中进行测试。Ft- 的传感器可能不能提供足够的灵敏度，用于神经元中稀疏或细微变化的功能成像，然而，生理学。为了解决这一问题，我们在目标3-4中建议开发第二个基因- 受控系统，其中神经元活动的标记物被酶转导并放大到ro- 可以使用强大的外源性造影剂读出的突发信号。这是一个雄心勃勃的计划。一旦完成，将改变研究人员研究大脑的方式。的 PI和他的实验室拥有丰富的经验，有效的合作记录和冒险精神。精神，这将使他们能够引入新一代的大脑测量和经验方法，神经科学