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Function and regulation of heterotrimeric G proteins in ciliogenesis and pathobiology of neurodevelopmental disorders

异源三聚体 G 蛋白在纤毛发生和神经发育障碍病理学中的功能和调节

基本信息

批准号：
10651317
负责人：
Inna Nechipurenko
金额：
$ 36.4万
依托单位：
WORCESTER POLYTECHNIC INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-05 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10651317
关键词：
Afferent Neurons Anatomy Behavioral Biological Assay Biomedical Research Caenorhabditis elegans Cell physiology Cells Cilia Data Defect Development Developmental Biology Experimental Models Foundations G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors GNAI1 gene GTP-Binding Protein alpha Subunits GTP-Binding Proteins Genes Genetic Genetic Diseases Goals Heterotrimeric GTP-Binding Proteins Human Image Impairment Intellectual functioning disability Investigation Knowledge Lead Literature Mammals Maps Mediating Membrane Modeling Molecular Morphogenesis Morphology Motor Mutation Nervous System Neuroanatomy Neurodevelopmental Disorder Neurologic Deficit Neurons Orthologous Gene Outcome Pathway interactions Patients Phenotype Property Protein Subunits Proteins Proteomics Public Health Publishing Regulation Research Role Sensory Shapes Signal Pathway Signal Transduction Signaling Protein Structure Surface Testing Therapeutic Work brain abnormalities candidate identification career cilium biogenesis genome editing in vivo innovation insight mutant neuron development neuropathology novel novel therapeutics protein function skills therapeutic target undergraduate student

项目摘要

PROJECT SUMMARY Many components of G-protein-coupled receptor (GPCR) signaling including heterotrimeric G (abg) proteins localize to primary cilia and modulate their morphology. Although cilia defects and dysregulated G protein signaling are associated with neurodevelopmental disorders (NDDs), the mechanisms by which G proteins regulate cilia morphogenesis or the extent to which disruption of ciliary Ga signaling contributes to NDDs remain largely unknown. The overall objective for this proposal is to define the molecular mechanisms by which RIC-8 – a highly conserved GPCR-independent activator of Ga proteins – shapes cilia morphology in sensory neurons. The overarching hypothesis for this application is that RIC-8 is dynamically trafficked to sensory cilia and controls ciliogenesis by potentiating Ga signaling. This hypothesis will be tested by pursuing two specific aims. Under the first aim, in vivo protein interaction assays and genome editing approaches will be used to mechanistically define the functional role of the RIC-8-Gai/o axis in controlling cilia morphogenesis. For the second aim, a synergistic approach comprised of genetic, imaging and in vivo proteomic approaches will be applied to identify molecular regulators of RIC-8 ciliary transport and function in sensory neurons. The proposed research is innovative because it uses a comprehensive approach to define a novel cellular function of RIC-8- Gai/o signaling in neuronal development. The proposed research is significant because it is expected to establish a strong scientific framework for investigations into the molecular composition and functions of the ciliary RIC-8- Gai/o signaling network(s) in C. elegans and vertebrate models and to determine how altered Ga-protein signaling may contribute to neurodevelopmental disorders.

项目总结