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Developing RNA therapeutics for TDP-43 proteinopathy in ALS/FTD

开发针对 ALS/FTD 中 TDP-43 蛋白病的 RNA 疗法

基本信息

批准号：
10710380
负责人：
Katie Elizabeth Copley
金额：
$ 4.77万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10710380
关键词：
ALS patients Affect Alzheimer&apos s disease related dementia Amyotrophic Lateral Sclerosis Behavior Binding Biochemical Biological Assay C-terminal Cell model Cells Cessation of life Clinical Cytoplasm Data Data Analyses Development Disease Electron Microscopy Environment Etiology Evolution Exhibits Fibroblasts Fostering Frontotemporal Dementia Goals Health In Vitro Laboratories Language Link Missense Mutation Modeling Molecular Motor Neurons Nerve Degeneration Neurodegenerative Disorders Neurons Neurosciences Nucleotides Pathologic Pathology Patients Pennsylvania Personality Physiology RNA RNA Binding RNA Splicing RNA-Binding Proteins Recombinants Research Personnel Role Solubility Specificity Symptoms TDP-43 aggregation Techniques Temporal Lobe Testing Therapeutic Toxic effect Training Universities Variant career cellular pathology collaborative environment crosslinking and immunoprecipitation sequencing design disease phenotype disorder subtype experimental study frontal lobe frontotemporal lobar dementia amyotrophic lateral sclerosis gain of function in vitro Assay insight loss of function motor impairment mutant neuron loss prevent protein TDP-43 stem success therapeutic RNA therapeutically effective transcriptome sequencing

项目摘要

PROJECT SUMMARY My long-term career goal is to tackle neurodegeneration as an academic researcher. Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), an Alzheimer's Disease Related Dementia (ADRD), are both fatal neurodegenerative disorders characterized by neuronal loss. ALS is primarily characterized by motor impairments stemming from loss of motor neurons, whereas the main symptoms of FTD include changes in personality, behavior, and language stemming from loss of cortical neurons in the frontal and temporal lobes. ALS and FTD exist on a disease spectrum, where some patients present with features of both diseases. A molecular hallmark shared by almost all ALS patients and approximately half of FTD patients is the pathological aggregation of the RNA-binding protein TDP-43. It has recently been established that the solubility of TDP-43 is increased by its binding to RNA. My preliminary data utilizing in vitro aggregation assays with purified TDP-43 indicate that missense mutations in TDP-43 can alter the ability of RNA to prevent aggregation of TDP-43. Based on these findings, I hypothesize that aberrant aggregation of TDP-43 in ALS/FTD models is due to alterations in TDP-43:RNA interactions. and that directly manipulating the RNA interactions of TDP-43 can rescue disease phenotypes. The goal of this proposal is to assess if differences in the RNA interactions of TDP-43 are present in disease by 1) examining the ability of short RNAs to prevent aggregation of disease-linked TDP-43 variants in vitro and 2) determining if there are alterations in the RNAs that TDP-43 binds to in ALS/FTD patient-derived neurons versus control neurons. The proposal also aims to 3) determine if administration of short RNAs that bind TDP-43 can rescue disease phenotypes in ALS/FTD patient-derived neurons. The proposed experiments will provide critically lacking information on the interactions between TDP-43 and RNA in disease as well as strategies to target these interactions therapeutically. The proposed experiments will substantially contribute to my training, allowing me to gain expertise in new techniques such as electron microscopy, crosslinking immunoprecipitation (CLIP), and sequencing data analysis. My training environment will foster success for the proposal, combining the biochemical expertise of the Shorter laboratory and the exceedingly collaborative environment at the University of Pennsylvania and within the Neuroscience Graduate Group. These studies will facilitate both my scientific and career goals by supporting my evolution into an academic researcher who develops therapeutics for patients with neurodegenerative disease.

项目总结