Investigating the pathomechanisms underlying Charcot-Marie-Tooth Disease

研究腓骨肌萎缩症的病理机制

• 批准号: 10541701
• 负责人: Julia Alexis Jones
• 金额: $ 3.48万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10541701
• 关键词: Address; Affect; Amino Acids; Amino Acyl-tRNA Synthetases; Antioxidants; Auditory system; Axon; Binding Sites; Biological Assay; Brain Stem; Cell Line; Cell Nucleus; Cell physiology; Cells; Charcot-Marie-Tooth Disease; Clinical; Cochlea; Cytosol; DNA Damage; Defect; Development; Disease; Educational process of instructing; Educational workshop; Enzymes; Epithelial; Exhibits; Family; Family member; Fibroblasts; Gene Expression; Gene Family; Genes; Genetic Transcription; Goals; HSPB1 gene; Hereditary Motor and Sensory Neuropathy Type I; Hereditary Motor and Sensory-Neuropathy Type II; Hindlimb; Human; Image; Impaired cognition; Inherited; Investigation; Link; Longitudinal Studies; Maps; Metabolism; Midbrain structure; Mitochondria; Modeling; Molecular; Molecular Profiling; Molecular Target; Morphology; Motor; Motor Neurons; Mus; Mutate; Mutation; Myelin Sheath; Neuroglia; Neurologic Effect; Neurons; Neurosciences; Nuclear; Nuclear Localization Signal; Organelles; Organism; Oxidative Stress; PMP22 gene; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Peripheral Nervous System Diseases; Persons; Phase; Phenotype; Physiological; Physiology; Play; Production; Property; Protein Biosynthesis; Proteins; Research; Research Project Grants; Role; Schwann Cells; Sensory; Signal Pathway; Specificity; Stress; Technical Expertise; Therapeutic; Tissue Sample; Transfer RNA; Transfer RNA Aminoacylation; Tyrosine-tRNA Ligase; United States; Writing; auditory pathway; axon injury; base; biological adaptation to stress; career; cell type; druggable target; fly; hearing impairment; in vivo; induced pluripotent stem cell; insight; kidney cell; knock-down; member; mitochondrial dysfunction; mouse model; mutant; response; sex; spiral ganglion; symposium; therapeutic development; transcriptome sequencing

PROJECT SUMMARY Charcot-Marie-Tooth (CMT) disease is a genetically and clinically heterogeneous group of inherited peripheral neuropathies that is characterized by damage to long motor and sensory axons. The overall goal of this project is to identify the molecular and cellular processes that are shared between different CMT genes to help address a common target for treatment for this currently incurable disease. Our lab extensively studies aminoacyl-tRNA synthetases (aaRS), the largest gene family involved in CMT, and discovered the nuclear function of one aaRS, TyrRS, was shown to be associated to CMT pathogenesis while acting as a transcriptional regulator under oxidative stress. Aim 1 sets out to understand how the nuclear aaRS function in oxidative stress response plays a role in mouse physiology and if it is the commonality between CMT-linked aaRS. Findings so far suggest nuclear TyrRS in mice leads to an increased metabolism and disruption in the auditory system. This proposal sets out to perform a longitudinal study to determine if the hearing loss is degenerative and where in the auditory pathway there is a defect (e.g., sensory epithelium, spiral ganglion, brainstem, midbrain) while also examining the molecular targets responsible using RNA-Sequencing on tissue samples. Additionally, we uncovered that CMT-linked aaRS share a similar nuclear localization response upon oxidative stress treatment in neuronal cells only. Aim 1 also sets out to investigate this apparent cell type specificity, examine more cell lines, and evaluate the factor responsible for the translocation property. More broadly, I want to understand the connection between multiple CMT genes and subtypes to have a holistic view of the cellular organelles and signaling pathways underlying CMT pathomechanisms. Therefore, in Aim 2 as a postdoctoral trainee I will study a range of CMT proteins across subtypes of varying phenotypes. Patient derived, induced pluripotent stem cells will be differentiated into two relevant CMT cell types for each mutant: motor neurons and Schwann cells. Because there is evidence suggesting mitochondrial defects and oxidative stress in some CMT subtypes, I will specifically investigate mitochondrial morphology, dynamics, and function using imaging and cell-based assays, as well as, exploring the levels of oxidate stress, stress-related damage, and potential pathways affected in CMT in a cell type specific manner. During this proposal, activities such as teaching, writing workshops, mastery of technical skills, and conference participation will be emphasized to equip me with the professional development needed for an independent career in neuroscience.

项目总结