Mechanisms of Neurodegeneration in CMT4B3: a Complex Pediatric Neurodevelopmental Disorder

CMT4B3 神经退行性变的机制：一种复杂的小儿神经发育障碍

基本信息

批准号：
10750509
负责人：
Elizabeth Haley Jacobs
金额：
$ 5.27万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
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：
2023-08-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10750509
关键词：
3-Dimensional Affect Alleles Autophagocytosis Axon Axonal Neuropathy Binding Biochemical Bioinformatics Biological Markers Central Nervous System Charcot-Marie-Tooth Disease Child Childhood Clinical Co-Immunoprecipitations Complex Cranial Nerves Cytoskeleton Data Data Set Defect Demyelinations Development Disease Drug usage Endosomes Exhibits Expression Profiling Face Fellowship Fluorescent Dyes Functional disorder Future Gene Expression Gene Expression Profile Gene Expression Profiling Genes Goals Homeostasis Human Image Imaging Techniques Immunofluorescence Immunologic Induced pluripotent stem cell derived neurons Inherited Inositol Intellectual functioning disability Intracellular Membranes Knowledge Lead Life Link Mass Spectrum Analysis Mediator Mission Modality Modeling Molecular Molecular Profiling Motor Neurons Mus Musculoskeletal Mutation National Institute of Child Health and Human Development Nerve Degeneration Neurodevelopmental Disorder Neurologist Neuromuscular Diseases Neurons Neuropathy Other Genetics Pathogenesis Pathologic Pathway interactions Patients Pattern Peptides Peripheral Nerves Peripheral Nervous System Peripheral Nervous System Diseases Phenotype Phosphatidylinositols Phosphoric Monoester Hydrolases Phosphotransferases Play Polyneuropathy Process Proteins Reproducibility Residual state Rodent Model Role Schwann Cells Scientist Signaling Molecule Spinal Symptoms System Therapeutic Toxic effect Training Validation Vertebral column Work analysis pipeline autosome axonal degeneration drug development drug discovery drug repurposing early childhood gain of function gene replacement gene therapy hereditary neuropathy high throughput screening induced pluripotent stem cell infancy inhibitor insight loss of function mouse model mutant myelination myotubularin nervous system development neurodevelopment neuronal cell body protein complex protein protein interaction recruit sensor stem targeted treatment therapeutic evaluation therapeutic target tool trafficking validation studies

项目摘要

Charcot-Marie-Tooth Disease type 4B3 (CMT4B3) is a rare, autosomal recessive hereditary axonal neuropathy, often presenting with severe regression of developmental milestones during infancy or early childhood. CMT4B3 has a wide clinical spectrum of symptoms. It ranges from an isolated demyelinating sensorimotor polyneuropathy to a complex neurodevelopmental phenotype with axonal neuropathy, cranial nerve involvement, intellectual disability and facial dysmorphism. Most children affected by CMT4B3 present with the severe phenotype. CMT4B3 is caused by mutations in the Sbf1 gene, resulting in disrupted function of the pseudo-inositol phosphatase, Myotubularin-Related Protein 5 (MTMR5). In this proposal, we focus on MTMR5, a developmentally important regulator of autophagy and endo-lysosomal trafficking, and its involvement in proper axonal homeostasis. MTMR5 is known to catalytically regulate and dictate the subcellular localization of Myotubularin- Related Protein 2 (MTMR2), an active phosphatase against phosphatidylinositol species. MTMR2 has known roles in Schwann cell homeostasis and loss of MTMR2 leads to a demyelinating neuropathy. MTMR5 was also identified as a neuron-specific suppressor of autophagy. Despite this knowledge, it is entirely unknown how disrupted function of MTMR5 leads to axonal degeneration during early childhood. Through the aims of this fellowship and using an established iPSC-derived motor neuron model of CMT4B3, I seek to clarify the biochemical role of MTMR5 in motor neurons and how loss of normal MTMR5 function results in axon degeneration early in development. In Aim 1 of this fellowship, I propose to utilize an iPSC-derived motor neuron model of CMT4B3 to understand the effects of MTMR5 loss on MTMR2, MTMR13, and phosphoinositide levels and discriminate if residual MTMR5 function causes toxicity in axons. In Aim 2, I seek to l gene expression profiling to characterize the downstream defects as a result of MTMR5 loss, which likely stem from MTMR5’s role in autophagy and endo-lysosomal trafficking. I plan to develop high-content image-based analyses to confirm expression profiling results and to create a much needed platform for drug discovery and gene therapy validation. Fully understanding the mechanisms underlying CMT4B3 is critical to the NICHD mission. Such knowledge is crucial for development and proper evaluation of therapeutic modalities that could help CMT4B3 patients. With this perspective, the proposed project is tailored to my training towards becoming a translational pediatric neurologist and scientist.

Charcot-Marie-Tooth疾病4B3型（CMT4B3）是一种罕见的常染色体隐性遗传轴突神经病，通常会在婴儿期发生严重的发育里程碑消退或幼儿。 CMT4B3具有广泛的症状临床范围。它的范围从一个孤立的脱髓鞘的感觉多发性神经病到具有轴突的复杂神经发育表型神经病，颅神经参与，智力残疾和面部畸形。大多数孩子受严重表型的CMT4B3影响。 CMT4B3是由SBF1突变引起的基因，导致伪肌醇磷酸酶，肌管蛋白相关蛋白的功能中断 5（MTMR5）。在此提案中，我们专注于MTMR5，这是自噬的发达重要调节剂和内糖体贩运及其参与适当的轴突稳态。已知MTMR5可以催化调节并决定肌蛋白蛋白的亚细胞定位相关蛋白2（MTMR2），一种针对磷脂酰肌醇种类的活性磷酸酶。 mtmr2具有在施旺细胞稳态中已知的作用和MTMR2的丧失导致神经病脱髓鞘。 MTMR5也被鉴定为自噬的神经特异性抑制剂。尽管有这些知识，完全未知MTMR5的功能如何导致早期轴突变性童年。通过该团契的目的，并使用已建立的IPSC衍生的电机神经元 CMT4B3的模型，我试图阐明MTMR5在运动神经元中的生化作用以及如何丢失正常的MTMR5功能导致发育早期的轴突变性。在该团契的目标1中，我建议利用CMT4B3的IPSC衍生的运动神经元模型来了解 MTMR2，MTMR13和磷酸肌醇水平的MTMR5损失，如果残留MTMR5，则分歧功能会导致轴突的毒性。在AIM 2中，我试图进行基因表达分析以表征 MTMR5损失导致下游缺陷，这可能源于MTMR5在自噬中的作用内糖体贩运。我计划开发基于图像的高含量分析以确认表达分析结果，并为药物发现和基因治疗验证创建急需的平台。完全了解CMT4B3的基础机制对于NICHD任务至关重要。这样的知识对于对可以帮助的治疗方式的发展和适当评估至关重要 CMT4B3患者。从这个角度来看，拟议的项目是为我的培训量身定制的成为翻译的小儿神经科医生和科学家。