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Synaptic dysglycosylation caused by the schizophrenia-risk variant in SLC39A8

SLC39A8 中精神分裂症风险变异引起的突触糖基化异常

基本信息

批准号：
10671675
负责人：
Robert G Mealer
金额：
$ 18.95万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
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：
2023-01-31 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10671675
关键词：
Adolescence Advisory Committees Affect Award Biological Biology Brain Brain Diseases Carbohydrates Cell Adhesion Molecules Cell-Adhesion Molecule Receptors Chromosome Pairing Clinical Trials Code Complement Complex Consultations Data Dendritic Spines Deposition Development Diagnostic Disease Dopamine Environment Enzymes Family Follow-Up Studies Fostering Functional disorder Future Genes Genetic Genetic Risk Genetically Engineered Mouse Genome Glutamate Receptor Glycobiology Glycoproteins Goals Heritability Homeostasis Human Impairment Individual Instruction Jordan K-Series Research Career Programs Knock-in Mouse Laboratories Length Link Lipids Manganese Maps Membrane Mendelian disorder Mentorship Metals Methods Missense Mutation Molecular Molecular Analysis Mus Mutation Neurologic Neurons Neurosciences Neurotransmitter Receptor Oral Pathogenesis Pathway interactions Peripheral Phenotype Plasma Play Polysaccharides Productivity Protein Glycosylation Proteins Proteomics Psychiatry Psychopharmacology Qualifying Research Research Personnel Residencies Rodent Role Schizophrenia Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Supplementation Synapses Techniques Testing Therapeutic Trace Elements Training Translating Translations Untranslated RNA Variant Vertebral column Work adhesion receptor career cofactor confocal imaging critical period density experience experimental study frontal lobe gamma-Aminobutyric Acid genetic association genome wide association study glycoproteomics glycosylation improved insight member mouse model neurodevelopment neuropsychiatric disorder neurotransmission novel novel therapeutics post-doctoral training pre-clinical preclinical safety psychogenetics receptor risk variant schizophrenia risk severe mental illness synaptic function synaptic pruning trafficking translational study trial design

项目摘要

PROJECT SUMMARY/ABSTRACT Schizophrenia is a severe mental illness with strong heritability, and advances in genetics have started to unravel the complex molecular underpinnings of this disorder. GWAS have identified over 250 loci linked to schizophrenia which are enriched near genes expressed in CNS neurons and involved in synaptic biology. Most schizophrenia-associated variants are in the non-coding region of the genome, though a small number result in a mutation within a known protein. The most significantly associated coding variant in schizophrenia GWAS is rs13107325 in SLC39A8, resulting in a missense mutation (A391T) in the eponymous manganese (Mn2+) transporter. Mn2+ transport by SLC39A8 is critical for glycosylation, the enzymatic attachment of carbohydrates to proteins and lipids, which is involved in neurodevelopment and synaptic function. Here, the applicant will investigate a novel molecular mechanism underlying increased schizophrenia risk in A391T carriers using a mouse model of genetic risk. Having shown that A391T mice have altered glycosylation of synaptic proteins, including neurotransmitter receptors and cell adhesion molecules, the applicant will test if altered glycosylation of these proteins changes their trafficking and localization, deposition of complement, and the number of dendritic spines in the frontal cortex (Aim 1). Next, he will attempt to reverse previously identified glycome changes with oral Mn2+ supplementation, overcoming impaired SLC39A8 transport from A391T. These studies will employ existing genetically engineered mouse lines, glycobiology techniques pioneered by the applicant, and cutting-edge neuroscience training in analysis of the synapse. Together, these aims will define the molecular alterations caused by A391T at the synapse and provide critical preclinical data for Mn2+ supplementation in carriers of A391T during critical periods of brain development and maturation. The applicant, Dr. Robert Mealer, is well qualified to execute the proposed experiments with his background in neuroscience, psychiatric genetics, and glycobiology. The four-year training plan will foster development towards independent investigator status and generate the preliminary data necessary for a future R01 application with clear therapeutic potential. He will continue his mentee relationships with Drs. Smoller and Cummings, while receiving additional training and mentorship from Dr. Morgan Sheng on the molecular analysis of the synapse. He has also enlisted Dr. Michael Aschner, a world leader on Mn2+ in the brain, and Dr. Maurizio Fava, a clinician researcher with extensive experience in psychopharmacology and trial design, as members of his research advisory committee. Finally, the collaborative research environment is ideal for furthering the applicant’s goal of becoming an independent researcher in academic psychiatry.

项目总结/文摘