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

• 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
• 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

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.

项目摘要/摘要 精神分裂症是一种严重的精神疾病，具有强大的遗传力，遗传学的进步已经开始 揭开该疾病的复杂分子基础。 GWAS已确定了250多个环境 精神分裂症富含在中枢神经系统神经元中表达并参与突触生物学的基因。 大多数精神分裂症相关的变体位于基因组的非编码区域，尽管很少 导致已知蛋白质中的突变。精神分裂症中最显着相关的编码变体 GWAS在SLC39A8中为RS13107325，导致借助锰的错义突变（A391T） （MN2+）转运蛋白。 MN2+ SLC39A8传输对于糖基化至关重要 碳水化合物与蛋白质和脂质有关，这些蛋白质与神经发育和突触功能有关。 在这里，申请人将研究一种新颖的分子机制，增加了精神分裂症的风险 A391T载体使用遗传风险的小鼠模型。表明A391T小鼠已经改变了糖基化 突触蛋白，包括神经递质接收器和细胞粘合剂分子，申请人将测试是否 这些蛋白质的糖基化改变改变了其贩运和本地化，完成的沉积和 额叶皮质中的树突状刺的数量（AIM 1）。接下来，他将尝试扭转先前确定的 通过补充口服MN2+的糖变化，从A391T克服了SLC39A8的受损受损。 这些研究将采用现有的基因工程小鼠系，糖生物学技术由 申请人和尖端的神经科学培训在突触分析中。这些目标将在一起 定义突触处A391T引起的分子改变，并为MN2+提供关键的临床前数据 在大脑发育和成熟的关键时期，A391T携带者补充。 申请人罗伯特·富师（Robert fearer）博士有资格执行拟议的实验，其背景 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 朝着独立研究者的身份，生成未来R01所需的初步数据 具有明显治疗潜力的应用。他将继续与博士的关系。虚张声器和 卡明斯（Cummings），同时在分子上接受摩根·尚（Morgan Sheng）博士的额外训练和心态 突触分析。他还邀请了MN2+的世界领导者Michael Aschner博士和博士 毛里齐奥·法瓦（Maurizio Fava）是一名临床研究人员 他的研究咨询委员会成员。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人员的目标。