Neuropathogenic Studies of Congenital Disorders of Glycosylation

先天性糖基化障碍的神经病理学研究

基本信息

批准号：
9979478
负责人：
Zhaolan Zhou
金额：
$ 44.6万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9979478
关键词：
Address Adopted Adult Alleles Animal Model Ataxia Atrophic Behavioral Blood Coagulation Disorders Brain Cell physiology Cells Cerebellar Nuclei Cerebellar degeneration Cerebellum Characteristics Childhood Communities Congenital cerebellar hypoplasia Congenital disorders of glycosylation Development Diagnosis Disease Disorder of neurometabolic regulation Embryo Enterobacteria phage P1 Cre recombinase Enzymes Epilepsy Exhibits Exons Failure Functional disorder Future Gene Delivery Genes Genetic Genetic Diseases Growth Heterozygote Impairment Injections Intellectual functioning disability Investigation Knock-in Knowledge Link LoxP-flanked allele Maintenance Mannose Mediating Missense Mutation Modeling Molecular Monosaccharides Morbidity - disease rate Mus Mutation Nervous system structure Neuroglia Neurologic Neurologic Deficit Neurons Nonsense Codon Ophthalmology Organ Pathogenesis Pathogenicity Pathology Pathway interactions Patients Pharmacology Phenotype Phosphomannomutase Protein Glycosylation Proteins Research Resources Role Seizures Source Symptoms Therapeutic Time Ursidae Family age related base behavioral phenotyping cell type experience glycosylation improved innovation insight interest link protein loss of function mouse model novel preclinical study programs stroke-like episode therapeutic development tool

项目摘要

Congenital disorders of glycosylation (CDG) are a group of neurometabolic disorders characterized by genetic defects in the highly conserved cellular glycosylation machinery. A majority of CDG patients have biallelic mutations in PMM2, a gene encoding the protein phosphomannomutase 2 required to activate mannose monosaccharides for N-linked protein glycosylation. PMM2-CDG patients suffer from multi-systemic involvement, and all patients uniformly suffer from neurological impairment that is prominent, progressive, and produces lifelong intellectual disability, ataxia and often seizures. Based on the genetic basis of CDG, we propose to establish and characterize a novel mouse model of PMM2-CDG to specifically investigate the function of PMM2 in neuronal and glial cells. We will also investigate the role of PMM2 in cerebellum development and function. With combined genetic, molecular, and behavioral approaches, we hope to not only reveal novel insight into the pathogenic mechanisms of CDG, but also to expedite the development of mechanism-based therapeutics to improve treatment. Moreover, our proposed study will provide the research community at large with innovative tools and resources to investigate the pathophysiology underlying a variety of glycosylation deficit-related disorders.

先天性糖基化障碍（CDG）是一组神经代谢障碍，其特征为高度保守的细胞糖基化机制的遗传缺陷。大多数 CDG 患者 PMM2 具有双等位基因突变，PMM2 是编码蛋白质磷酸甘露糖变位酶 2 所需的基因激活甘露糖单糖进行 N 连接蛋白糖基化。 PMM2-CDG 患者患有多系统受累，所有患者均存在神经功能障碍显着、进行性，并导致终生智力障碍、共济失调和经常癫痫发作。基于基于 CDG 的遗传基础，我们建议建立并表征 PMM2-CDG 的新型小鼠模型专门研究 PMM2 在神经元和神经胶质细胞中的功能。我们还将调查 PMM2 在小脑发育和功能中的作用。结合遗传、分子和行为方法，我们希望不仅揭示 CDG 致病机制的新见解，还要加快开发基于机制的疗法以改善治疗。而且，我们提出的研究将为整个研究界提供创新工具和资源研究各种糖基化缺陷相关疾病的病理生理学。