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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.

项目概要/摘要精神分裂症是一种严重的精神疾病，具有很强的遗传性，遗传学的进步已经开始揭示这种疾病复杂的分子基础。 GWAS 已识别出超过 250 个与精神分裂症在中枢神经系统神经元表达的基因附近富集并参与突触生物学。大多数与精神分裂症相关的变异位于基因组的非编码区域，尽管少数导致已知蛋白质内的突变。精神分裂症中最显着相关的编码变异 GWAS 是 SLC39A8 中的 rs13107325，导致同名锰中出现错义突变 (A391T) (Mn2+)转运蛋白。 SLC39A8 的 Mn2+ 转运对于糖基化至关重要，糖基化是 Mn2+ 的酶促附着碳水化合物转化为蛋白质和脂质，参与神经发育和突触功能。在这里，申请人将研究精神分裂症风险增加的新分子机制使用遗传风险小鼠模型的 A391T 携带者。已证明 A391T 小鼠的糖基化发生了改变突触蛋白，包括神经递质受体和细胞粘附分子，申请人将测试是否这些蛋白质糖基化的改变改变了它们的运输和定位、补体的沉积，以及额叶皮质中树突棘的数量（目标 1）。接下来，他将尝试扭转先前确定的口服 Mn2+ 补充剂会改变糖组，克服 A391T 转运受损的 SLC39A8。这些研究将采用现有的基因工程小鼠品系，以及由申请人以及突触分析方面的尖端神经科学培训。这些目标共同将定义 A391T 在突触处引起的分子改变，并提供 Mn2+ 的关键临床前数据在大脑发育和成熟的关键时期补充 A391T 携带者。申请人 Robert Mealer 博士具有以下背景，完全有资格执行所提议的实验：神经科学、精神遗传学和糖生物学。四年培训计划将促进发展获得独立调查员身份并生成未来 R01 所需的初步数据具有明显治疗潜力的应用。他将继续与博士保持学员关系。斯莫勒和卡明斯，同时接受摩根盛博士关于分子生物学的额外培训和指导突触分析。他还聘请了大脑 Mn2+ 领域的世界领先者 Michael Aschner 博士和 Dr. Michael Aschner。 Maurizio Fava 是一位临床研究员，在精神药理学和试验设计方面拥有丰富的经验，他的研究顾问委员会的成员。最后，协作研究环境非常适合促进申请人成为学术精神病学独立研究员的目标。