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Mapping molecular pathways that control prion metabolism

绘制控制朊病毒代谢的分子途径

基本信息

批准号：
10539945
负责人：
Surachai Supattapone
金额：
$ 68.66万
依托单位：
DARTMOUTH COLLEGE
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：
2022-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10539945
关键词：
Anabolism Animal Model Atlases Biochemical Genetics Biochemical Pathway Biological Bovine Spongiform Encephalopathy Brain Brain Diseases Brain region Cell Line Cells Cellular biology Chronic Wasting Disease Clustered Regularly Interspaced Short Palindromic Repeats Creutzfeldt-Jakob Syndrome Fluorescence-Activated Cell Sorting Genes Genetic Screening Genomic Library Genomic approach Genomics Human Individual Induced pluripotent stem cell derived neurons Infection Knock-out Knowledge Libraries Maps Metabolic Metabolic Pathway Metabolism Methods Modeling Molecular Molecular Conformation Mus Neurodegenerative Disorders Neurons Pathway interactions Pattern PrP PrPSc Proteins Predisposition Prion Diseases Prions Scrapie Sorting - Cell Movement Surface Techniques Testing Time Undifferentiated Work base cofactor conformer experimental study metabolic profile misfolded protein new therapeutic target next generation sequencing novel novel strategies targeted treatment trafficking whole genome

项目摘要

Project summary Mammalian prion diseases, such as Creutzfeldt-Jakob disease (CJD), Chronic Wasting Disease (CWD), bovine spongiform encephalopathy (BSE), and scrapie, are a group of infectious neurodegenerative disorders caused by the autocatalytic conversion of the host-encoded prion protein, PrPC, into a group of misfolded, infectious conformers collectively termed PrPSc. Multiple lines of evidence from biochemical, genetic, and cell biological studies suggest that PrPC and PrPSc employ specific pathways for biosynthesis, trafficking, and degradation in living cells. However, full elucidation of these pathways has been hindered the lack of tractable model organisms for genetic screening. To overcome this obstacle, we recently developed methods to detect both PrPC and PrPSc in brain-derived CAD5 cells using fluorescence-activated cell sorting (FACS). We will use these sensitive sorting methods to perform CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 whole genome library screens in CAD5 cells infected with different prion strains. These studies will be the first to fully map the molecular pathways that control the biosynthesis, trafficking, and degradation of both PrPC and PrPSc molecules, and thereby greatly advance our fundamental knowledge of prion cell biology. Our unbiased screens will also reveal the rate limiting steps of prion formation and clearance, thereby identifying the most susceptible targets for drug therapy.

项目总结