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Cytoskeletal mechanisms of dendrite arbor shape development

树突乔木形状发育的细胞骨架机制

基本信息

批准号：
10649463
负责人：
GIORGIO A ASCOLI
金额：
$ 30.13万
依托单位：
GEORGIA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10649463
关键词：
3-Dimensional Address Afferent Neurons Architecture Automobile Driving Behavior Biochemistry Cell physiology Cognition Communities Complex Computational Technique Computer Simulation Cytoskeletal Modeling Cytoskeleton Data Dendrites Development Developmental Process Dimensions Disease Drosophila genus F-Actin Foundations Functional disorder Funding Genetic Goals Health Image Imaging Techniques Link Location Mediating Microtubules Modeling Modification Molecular Molecular Genetics Molecular Target Morphology Nervous System Neurodegenerative Disorders Neurons Neurosciences Pathway interactions Phosphoric Monoester Hydrolases Process Property Protein Phosphatase 2A Regulatory Subunit PR53 Proteins Regulation Regulatory Pathway Resolution Role Route Shapes Signal Transduction Specific qualifier value Structure System Testing Time Work cellular imaging chaperonin CCT computer studies computerized tools design genetic regulatory protein in vivo innovation insight meter nervous system disorder neural neurogenetics neuroinformatics neuropathology neurotoxic novel open source programs protein aggregation protein folding proteostasis reconstruction spatiotemporal synergism tool

项目摘要

Abstract The specification and dynamic modification of subtype specific dendritic architecture not only dictates how distinct classes of neurons form functional connections with other neurons, but also directly influences subtype- specific computational properties. Dendritic form, and by extension function, is chiefly mediated by subcellular organization and dynamics of cytoskeletal components. Thus, identifying molecular factors and cellular processes that regulate subtype specific dendritogenesis is essential to our understanding of the mechanistic links between cytoskeletal organization and neuronal form and function in both health and neuropathologies. Protein homeostasis, or proteostasis, is essential to cellular health and as a surveillance system against neurotoxic aggregates implicated in numerous neurodegenerative disease states. Despite this importance, relatively little is known regarding the normal developmental roles of proteostasis regulatory pathways in driving dendritic diversity or subtype-specific cytoskeletal organization. Our work in the previous funding cycle provided the foundations for combining neurogenetic manipulations, in vivo spatio-temporal multichannel imaging and computational techniques for multichannel and time-varying neuronal reconstructions of subtype specific dendritic cytoskeletal architectures. This strategy yielded novel insights into local cytoskeletal control mechanisms regulating dendritic arbor diversity that could not have been solely predicted or quantitatively characterized without the synergy of these approaches. For this next funding cycle, we hypothesize that the evolutionarily conserved PP2A phosphatase and TRiC/CCT chaperonin complexes function as essential proteostasis regulators that exert control over the spatiotemporal organization and dynamics of cytoskeletal components underlying subtype-specific dendritic arbor diversity. To investigate this core hypothesis, we propose the following tightly linked aims. First, we will elucidate the mechanistic role(s) of the PP2A phosphatase and TRiC/CCT chaperonin complex in directing subtype specific dendritic arborization. Second, we will identify the functional requirements and putative molecular targets of PP2A and TRiC/CCT in regulating subtype specific dendritic cytoskeletal architecture and dynamics. Third, we will conduct computational studies of dendritic morphology and spatio-temporal cytoskeletal distributions that directly integrates and synergizes with the first two aims thereby generating a closed-loop investigational system. These studies will not only reveal novel molecular mechanisms driving cytoskeletal organization and dynamics that functionally contribute to the emergence of diverse dendritic arbors, but also develop and disseminate neuroinformatic tools and data of broad impact to the neuroscience community.

摘要