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Selective neuronal silencing to study cognitive decline in Alzheimer's disease

选择性神经元沉默研究阿尔茨海默病的认知能力下降

基本信息

批准号：
7429627
负责人：
JOANNA L JANKOWSKY
金额：
$ 22.2万
依托单位：
CALIFORNIA 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 2008-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7429627
关键词：
3&apos Splice Site Actins Action Potentials Acute Address Adopted Adult Adverse effects Affect Age Agonist Alzheimer&apos s Disease Amygdaloid structure Amyloid Amyloid beta-Protein Precursor Amyloid deposition Amyloidosis Animal Behavior Animal Model Animals Antimitotic Agents Anxiety Appearance Area Astrocytes Atlases Axon Bacterial Artificial Chromosomes Behavior Behavioral Binding Biochemical Biological Assay Birth Brain Breeding Bromodeoxyuridine Caenorhabditis elegans Cell Death Cell Line Cell Nucleus Cell division Cells Cephalic Cessation of life Characteristics Chemicals Cherry - dietary Chloride Channels Cholinergic Agents Chromosome Pairing Chromosome abnormality Class Clinical Code Cognitive Collaborations Communities Complementary DNA Computer information processing Condition Corpus striatum structure Cultured Cells Cytoplasm Cytoplasmic Granules Cytostatics DNA Sequence Rearrangement Data Databases Daughter Dementia Deposition Depth Development Diagnosis Disadvantaged Discrimination Disease Distant Dose Drug usage Early Intervention Ectopic Expression Educational process of instructing Electrophysiology (science)Elements Embryo Embryonic Development Emotional Emotions Engineering Enhancers Ensure Equilibrium Estrogen Analogues Estrogen Receptors Estrogens Excision FOS gene Facility Construction Funding Category Failure Family Picornaviridae Fiber Fire - disasters Fright Functional disorder Future G-Protein-Coupled Receptors Ganciclovir Gene Expression Genes Genetic Genetic Recombination Genetic Transcription Genomic Segment Genomics Glutamates Goals Harvest Heart Hippocampus (Brain)Hour Human Image Immune response Immunohistochemistry Impaired cognition Impairment In Vitro Indium Individual Inflammation Inflammatory Response Inherited Injection of therapeutic agent Injury Intermediate Filaments Internal Ribosome Entry Site Interneurons Intervention Introns Investments Ion Channel Ivermectin Knowledge Label Laboratories LacZ Genes Lateral Learning Left Lesion Life Ligands Light Link Localized Location Long-Term Potentiation Mammalian Cell Mediating Membrane Potentials Memory Memory impairment Messenger RNA Methods Microtubule-Associated Proteins Mind Minor Mitotic Modeling Morphology Mus Muscimol Mutant Strains Mice Myocardial Infarction Names Nature Neomycin Neuroanatomy Neurobehavioral Manifestations Neurobiology Neuroblastoma Neurodegenerative Disorders Neurologic Neurologist Neuronal Dysfunction Neurons Neurosciences Newborn Infant Nucleic Acid Regulatory Sequences Numbers Older Population Open Reading Frames Operative Surgical Procedures Outcome Output Parkinson Disease Partner in relationship Pathogenesis Pathology Pathway interactions Patients Pattern Peptides Perforant Pathway Performance Peripheral Personal Communication Personal Satisfaction Pharmaceutical Preparations Pharmacologic Substance Pharmacological Treatment Phase Placement Plague Pliability Population Population Study Positioning Attribute Postdoctoral Fellow Preparation Prevention Process Production Property Protein Engineering Protein Overexpression Protein S Proteins Publications Publishing Qualifying RNA Splicing Range Rattus Receptor Gene Recovery Regulatory Element Reporter Reporting Reproducibility Research Residual state Resolution Resources Rewards Rodent Role Route Science Seizures Senile Plaques Siblings Signal Transduction Site Sleep Slice Solutions Southern Blotting Specific qualifier value Specificity Staging Standards of Weights and Measures Structure Students Study models Symptoms Synapses System Tamoxifen Target Populations Techniques Technology Testing Tetanus Helper Peptide Tetanus Toxin Tetracycline Tetracyclines Therapeutic Therapeutic Intervention Thinking Thymidine Kinase Time Toxin Training Transcript Transcriptional Activation Transfection Transgenes Transgenic Animals Transgenic Mice Transgenic Model Transgenic Organisms Treatment Protocols Upper arm Variant Veins Vertebral column Vesicle Viral Viral Vector Week Woodchuck Hepatitis B Virus Work Zebrafish amyloid pathology basal forebrain base behavior test blastocyst blastomere structure body system cholinergic cholinergic neuron clinically relevant cognitive function conditioned fear daughter cell day dentate gyrus design desire disease characteristic drug-sensitive embryonic stem cell entorhinal cortex experience feeding functional restoration glutamate-gated chloride channel granule cell healthy aging hippocampal pyramidal neuron homologous recombination human disease improved in vivo innovation insight interest inward rectifier potassium channel irradiation killings lateral ventricle ligand gated channel link protein mature animal memory retention migration morris water maze mossy fiber mouse model nerve stem cell nestin protein neuroblast neurogenesis neuropathology neurotransmitter release news next generation novel peptide A prevent progenitor promoter protein expression receptor receptor expression recombinase relating to nervous system research study response restoration selective expression skills stem cells stoichiometry success tool transgene expression vector

项目摘要

Our understanding of neurodegenerative diseases is currently hindered by lack of a firm neurobiological link between the patient's symptoms and the underlying neuropathology. To advance, we must identify not only key biochemical changes, but also how these changes alter the function of specific circuits to cause neurological symptoms. I seek to understand how impairment of particular circuits initiates early symptoms of Alzheimer's disease (AD), and how addition of further dysfunction leads to the disease's ultimate decline. I will apply a new method of selective neuronal silencing in transgenic mice to examine the behavioral impact of inactivating neuronal circuits damaged in AD. My postdoctoral laboratory has developed a novel chloride channel that responds specifically to ivermectin by producing hyperpolarization that results in selective, reversible suppression of neuronal activity. I will use my expertise in transgenic technology to create a mouse in which the ivermectin channel is conditionally expressed under control of Cre recombinase. Mating this mouse to animals expressing Cre in selected neuronal populations will allow those cells to be silenced with systemic ivermectin. My goal is to explore the function of adult-born hippocampal neurons, as this population is severely diminished in mouse models for AD. I will examine the role of these cells in learning and memory by selectively silencing them at critical times in the acquisition, consolidation, and recall of new information. Additional studies will address the effect of silencing on the migration, morphology, and survival of these adult-born cells. My long-term plans are to examine the behavioral impact of silencing other circuits damaged later in the course of disease to understand how diminished activity in multiple domains results in the progressive cognitive decline of AD. In the process, I will generate a transgenic mouse for selective neuronal silencing that will be broadly useful to the neuroscience community.

我们对神经退行性疾病的了解目前由于缺乏确凿的证据而受到阻碍患者症状和潜在神经病理之间的神经生物学联系。至为了取得进展，我们不仅必须确定关键的生化变化，而且必须确定这些变化是如何改变的引起神经症状的特定回路的功能。我试图理解为什么阿尔茨海默病(AD)的早期症状是由特定回路的损伤引起的，以及进一步的功能障碍会导致这种疾病的最终衰落。我要用一种新方法在转基因小鼠中选择性神经元沉默的研究阿尔茨海默病中受损的神经元回路失活。我的博士后实验室已经开发出一种通过产生超极化对伊维菌素产生特异性反应的新型氯离子通道这会导致选择性的、可逆的神经元活动抑制。我将利用我的专业知识转基因技术创造了一种伊维菌素通道有条件地在Cre重组酶控制下表达。将这只小鼠与表达Cre的动物交配选定的神经元群体将允许这些细胞用全身伊维菌素沉默。我的目标是探索成年出生的海马神经元的功能，因为这一群体严重在AD的小鼠模型中减少。我将研究这些细胞在学习和学习中的作用通过在获取、巩固和回忆的关键时刻选择性地使他们保持沉默来记忆新的信息。其他研究将解决沉默对迁徙的影响，这些成体细胞的形态和存活情况。我的长期计划是研究使病程后期受损的其他回路沉默对行为的影响理解在多个领域中活动减少如何导致渐进性认知 AD的衰退。在这个过程中，我将产生一只用于选择性神经元的转基因小鼠沉默，这将对神经科学界广泛有用。