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Study on PFN1 Pathobiology Using Rat Models

利用大鼠模型进行 PFN1 病理学研究

基本信息

批准号：
9912205
负责人：
xugang xia
金额：
$ 59.1万
依托单位：
FLORIDA INTERNATIONAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-15 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9912205
关键词：
Affinity Amyotrophic Lateral Sclerosis Animal Model Animals Binding Biological Markers Biology Cells Complementary DNA Denervation Disease Disease Progression Disease model Exhibits Gene Expression Genes Genetic Genome Genomics Hereditary Disease Human Impairment Inherited Invertebrates Knock-in Knock-out Link Longevity Modeling Molecular Molecular Chaperones Monitor Motor Motor Neurons Mouse Strains Mus Mutation Nerve Degeneration Neuraxis Nucleotides Pathogenesis Pathogenicity Pathway interactions Patients Pattern Phenotype Physiological Pilot Projects Rat-1 Rattus Research Rodent Study models Therapeutic Effect Transgenes Transgenic Mice Transgenic Model Transgenic Organisms Treatment Efficacy Vertebrates aged disease phenotype disease-causing mutation effective therapy gene function human disease human model mutant nervous system disorder neuron loss overexpression prefoldin preservation profilin 1 promoter protein TDP-43 protein aggregation rat genome skeletal muscle wasting sporadic amyotrophic lateral sclerosis superoxide dismutase 1 transgene expression

项目摘要

Pathogenic mutation of profilin 1 (PFN1) is causative to amyotrophic lateral sclerosis (ALS). PFN1 has been examined extensively on its biology and recently on its pathobiology, but how PFN1 mutation causes the disease remains to be determined. A critical step towards understanding a disease gene is determining the overall effect of pathogenic mutation on the gene function at both systemic and molecular levels. ALS is a neurological disease and thus the overall effect of pathogenic mutation on PFN1 function must be determined in a vertebrate animal model because the complexity of the human central nervous system cannot be adequately simulated in cells or invertebrate animals. An effective animal model for ALS should meet at least three criteria: recapitulate the cardinal phenotypes of ALS including progressive degeneration of both upper and lower motor neurons and denervation atrophy of skeletal muscles; manifest the middle or late onset of ALS phenotypes that is common to sporadic and most inherited ALS; and display a differentiated disease phenotype between wild-type and mutant transgenic lines. An ideal animal model for human disease is gene knockin in which a single disease-causing mutation is introduced into the animal genome such that the pathogenic mutation is expressed at physiological levels and in intrinsic patterns, simulating the patterns and zygosities of gene expression that are observed in patients. As animals commonly used to model human diseases (i.e. mice and rats) have a shorter life span (2-3 years at maximum) than human (80 years on average), expression of a disease gene at physiological levels may not be sufficient to induce a full spectrum of disease phenotypes. Therefore, gene-overexpressing models (i.e. transgenics) are often used as the substitutes of knockin models for studying inherited diseases. To unravel the overall effect of pathogenic mutation on the PFN1 functions, we have created PFN1 transgenic rats that meet the criteria of effective ALS model and also have created PFN1 knockin rats that express PFN1 mutation from its endogenous locus. The knockin rats differ from their wildtype littermates in a single nucleotide examined. Any phenotypes detected in the knockin rats must result from the pathogenic mutation introduced. Using PFN1 transgenic and knockin rats as complementary models, we are going to determine the overall effect of pathogenic mutation on PFN1 function at both systemic and molecular levels, revealing the authentic mechanisms by which PFN1 mutation causes the disease. Our PFN1 rat models will be the second effective ALS model after SOD1 transgenic rodents and thus will meet the compelling need of ALS research in that disease mechanisms and therapeutic efficacies discovered in one model must be determined in the other models for the convergence and divergence among varying ALS genes because convergent disease mechanisms revealed in genetic ALS models will have a better prediction of sporadic ALS.

PFN1致病性突变是肌萎缩性侧索硬化症（ALS）的病因。PFN1已经被