Identifying the function of alternatively spliced TDP43 isoforms and contribution to disease

确定选择性剪接 TDP43 亚型的功能及其对疾病的影响

• 批准号: 10748166
• 负责人: Megan Dykstra
• 金额: $ 4.09万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10748166
• 关键词: ALS patients; Adaptor Signaling Protein; Affect; Alternative Splicing; Amino Acids; Amyotrophic Lateral Sclerosis; Antisense Oligonucleotides; Binding; Bioinformatics; Biology; C-terminal; Cell Nucleus; Communication; Coupled; Cytoplasm; Cytoplasmic Granules; DNA; Data; Data Analyses; Disease; Event; Exhibits; Experimental Designs; Fluorescent in Situ Hybridization; Frontotemporal Dementia; G3BP1 gene; Genes; Glycine; Goals; Homeostasis; Immunoprecipitation; Individual; Induced pluripotent stem cell derived neurons; Introns; Investigation; Label; Laboratories; Length; Measures; Mediating; Messenger RNA; Metabolic; Methods; Molecular; Motor Neurons; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; Nuclear; Nuclear Export; Nuclear Protein; Organelles; Pathogenesis; Pathology; Pathway interactions; Patients; Population; Production; Protein Isoforms; Proteins; Proteomics; RNA; RNA Binding; RNA Degradation; RNA Recognition Motif; RNA Splicing; RNA Stability; RNA-Binding Proteins; Regulation; Research Personnel; Response Elements; Ribonucleoproteins; Role; Services; Set protein; Testing; Toxic effect; Transcript; Translational Repression; Translations; Variant; Work; career; cell type; comorbidity; crosslink; frontotemporal lobar dementia amyotrophic lateral sclerosis; immunocytochemistry; insight; knock-down; mRNA Decay; mRNA Precursor; neuron loss; next generation; next generation sequencing; novel; novel therapeutic intervention; protein TDP-43; protein protein interaction; recruit; skills; stress granule; success; training opportunity; transcriptome sequencing

PROJECT SUMMARY Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are related, often comorbid, neurodegenerative disorders with no available disease-modifying therapies. In over 95% of ALS patients, and 50% of FTD patients, affected neurons exhibit cytoplasmic mislocalization and accumulation of TDP43 (transactive response element DNA/RNA binding protein, 43 kDa). Mutations in TARDBP, the gene encoding TDP43, also cause familial forms of ALS and FTD, highlighting an integral contribution of TDP43 to these conditions. Even so, the mechanisms underlying TDP43 mislocalization in disease remain unclear. Recent evidence from our laboratory suggests that TDP43 mislocalization may be due to the production of alternatively spliced, shortened (s)TDP43 isoforms that are actively exported from the nucleus and prone to aggregation. sTDP43 isoforms are also evolutionarily conserved, but their regulation and function remain fundamentally unknown. This proposal seeks to elucidate the distinct function of sTDP43 isoforms and their potential contribution to disease by (i) defining the native transcript and protein interactors for sTDP43; and (ii) investigating a potential role for sTDP43 in regulating RNA stability. In so doing, these studies may reveal new pathways responsible for TDP43 mislocalization and neurodegeneration ALS and FTD. Additionally, it will enable me to develop essential skills in bioinformatics, proteomics, experimental design, data analysis, and scientific communication that will be critical for my success in my intended career as an independent investigator focused on the molecular underpinnings of neurodegeneration.

项目总结