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Investigating the synaptic pathology of Autism

研究自闭症的突触病理学

基本信息

批准号：
10053341
负责人：
Stephen Edward Paucha Smith
金额：
$ 54.53万
依托单位：
SEATTLE CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-01 至 2022-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10053341
关键词：
Acute Affect Agonist Animal Model Animals Behavior Behavioral Binding Characteristics Chemicals Chemosensitization Co-Immunoprecipitations Complex DNA Sequence Alteration Data Disease Drug Targeting Equilibrium Feedback Fragile X Syndrome Gene Mutation Gene Proteins Genes Genetic Models Genetic study Glutamate Receptor Glutamates Goals Homeostasis Knock-out Link Longevity Measurement Metabotropic Glutamate Receptors Modeling Molecular Morphology Mutation N-Methyl-D-Aspartate Receptors N-Methylaspartate Neurodevelopmental Disorder Neurons Organism Output Pathogenesis Pathologic Pathology Pattern Pharmaceutical Preparations Physiological Process Protein Engineering Proteins Publishing Risk Science Signal Transduction Slice Stereotyping Structure Synapses System Technology Testing Therapeutic Translating UBE3A gene Variant autism spectrum disorder base design gene product graph theory in vitro Assay information processing insight kinase inhibitor link protein mathematical model member mouse model network models new technology novel overexpression predictive modeling protein complex protein function response scaffold small molecule stem synaptic function targeted treatment therapeutic target tool transmission process vector

项目摘要

PROJECT SUMMARY Genetic mutations that confer autism risk often occur in genes that are expressed at the glutamate synapse. The protein products of these genes form a highly interconnected protein interaction network (PIN), and represent attractive therapeutic targets since they are expressed throughout the lifespan and can be acutely targeted with small molecule drugs. However, the dynamic, network-scale behavior of this PIN in normal or disease states is poorly understood. Here, we apply a novel PIN-mapping technology, quantitative multiplex co-immunoprecipitation, to explore the input-output relationships of an autism-linked PIN at the glutamate synapse as it responds to physiological inputs. Our target system is a 20-member PIN, consisting of glutamate receptors, scaffolds, and signal transduction molecules; mutations in the genes encoding all target proteins have been genetically linked to autism. We first show that, in wild-type animals, our target PIN changes its pattern of co-associations in a stereotyped manner in response to acute stimulation with KCl or glutamate, using cultured neurons or acute slices. We then model the input-output relationships of the PIN system, and demonstrate that the PIN produces specific, recognizable signatures in response to stimulation through the mGluR or NMDA receptors. In the context of physiological glutamate stimulation, the PIN integrates the two inputs to produce a coordinated cellular response- potentiation or de-potentiation. Based on these and other preliminary observations and published data, we propose that mutations that contribute to autism risk disrupt information flow through this PIN, such that the balance between LTP-like potentiation and LTD-like depotentiaion is altered, ultimately leading to an organism-level imbalance between excitation and inhibition. We will test this hypothesis by modeling the PIN response to mGluR or NMDA stimulation in three distinct, well-characterized animal models of autism- the Fragile X knockout, Shank3 knockout, and Ube3a overexpressing models. We will characterize the input-output relationships for mGluR or NMDA stimulation, and mathematically model their integration using a vector transformation model in principal component space. We will define specific mechanisms by which autism-linked mutations disrupt either input-output relationships, or disrupt signal integration in the context of physiological stimulation. In addition, we will treat two of our animal models (Shank3 and Fragile X) with drugs that have been previously demonstrated to rescue autism- like behaviors. We will model the response of the PIN to the drug with or without concurrent stimulation to define a PIN signature associated with behavioral rescue. In summary we propose to (1) define normal information flow through a PIN consisting of the protein products of autism-liked genes; (2) define how information flow is disrupted in mouse models of autism, with the goal of understanding the system sufficiently to design targeted drug treatments and (3) define how the PIN responds to drugs that correct behavior, which could serve as a template for the design of PIN-modifying treatments to restore normal synaptic function.

项目总结