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.

腓骨肌萎缩症 4B3 型 (CMT4B3) 是一种罕见的常染色体隐性遗传病轴突神经病，通常表现为婴儿期发育里程碑的严重退化 CMT4B3 具有广泛的临床症状，包括孤立的症状。脱髓鞘性感觉运动性多发性神经病发展为轴突复杂的神经发育表型神经病变、脑神经受累、智力障碍和面部畸形。受 CMT4B3 影响的严重表型是由 Sbf1 突变引起的。基因，导致假肌醇磷酸酶、肌管蛋白相关蛋白的功能破坏 5 (MTMR5) 在本提案中，我们重点关注 MTMR5，它是自噬的发育重要调节因子。和内溶酶体运输，及其参与适当的轴突稳态。已知 MTMR5 可以催化调节和决定肌管蛋白的亚细胞定位相关蛋白 2 (MTMR2) 是一种针对 MTMR2 的活性磷酸酶。 MTMR2 在雪旺细胞稳态中的已知作用和缺失会导致脱髓鞘性神经病。 MTMR5 也被认为是一种神经元特异性自噬抑制因子。完全不知道 MTMR5 的功能破坏如何导致早期轴突变性通过该奖学金的目标并使用已建立的 iPSC 衍生的运动神经元。 CMT4B3 模型中，我试图阐明 MTMR5 在运动神经元中的生化作用以及如何丧失正常的 MTMR5 功能会导致发育早期的轴突变性。在本研究的目标 1 中，我建议利用 iPSC 衍生的 CMT4B3 运动神经元模型来了解 MTMR2、MTMR13 和磷酸肌醇水平上的 MTMR5 丢失以及残留 MTMR5 的区分功能导致轴突毒性在目标 2 中，我寻求基因表达谱来表征。 MTMR5 丢失导致下游缺陷，这可能源于 MTMR5 在自噬和我计划开发基于图像的高内涵分析来确认表达。分析结果并创建药物发现和基因治疗验证急需的平台。充分了解 CMT4B3 的潜在机制对于 NICHD 的任务至关重要。知识对于开发和正确评估治疗方式至关重要，这些方式可以帮助从这个角度来看，拟议的项目是针对我的培训量身定制的。成为一名转化儿科神经学家和科学家。