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Drug target identification using CRISPRi/a screening

使用 CRISPRi/a 筛选识别药物靶点

基本信息

批准号：
10006378
负责人：
Luke Gilbert
金额：
$ 22.45万
依托单位：
BIOIO, LLC
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10006378
关键词：
Alzheimer&apos s Disease Antineoplastic Agents Biochemical Genetics Biological Biological Assay Biology Businesses CRISPR interference Categories Cations Cell Line Cell model Cells Clinic Clustered Regularly Interspaced Short Palindromic Repeats Diabetes Mellitus Diagnostic Digestion Disease Drug Industry Drug Screening Drug Targeting Enzymes Failure Feedback Fluphenazine Foundations Gene Expression Genes Genetic Screening Genome Genomics Glyburide Healthcare Industry Hepatocyte Human Human Resources Industrialization Industry Collaboration K-562 K562 Cells Knowledge Libraries Liver Liver diseases Medicine Metabolic Modeling Molecular Molecular Mechanisms of Action Molecular Target Muscle Muscle Cells Neurons Patients Pharmaceutical Preparations Phase Phenothiazines Phenotype Phosphoric Monoester Hydrolases Phosphorylation Site Physiological Preparation Process Production Protocols documentation Publishing Reagent Services Technology Testing Therapeutic Threonine Time Traction Trypsin Ursidae Family Vision Work base cell type chronic myeloid leukemia cell cost cost effective drug development drug discovery genetic approach genome wide screen genome-wide improved in vivo interest novel therapeutics preservation research and development restriction enzyme screening side effect success

项目摘要

ABSTRACT As phenotypic screening makes a comeback in drug discovery, its major issue is drug target identification. There aren’t good generalizable approaches to do target identification for compounds of interest. Identifying how a new drug works at the molecular level is critical for improving it, which is often needed to give it the best chance of ultimately being both safe and effective in patients. In this proposal, we demonstrate a genome-wide CRISPRi/a screening process in human cells that readily identifies the molecular target(s) for drugs of interest. We present preliminary evidence it can also identify alternative targets for the disease indication for the drug as well as potential side effect targets. We demonstrate this screening process can be applied to drugs for diverse diseases. Thus, it has the potential to improve the number of drugs that make it through drug development pipelines that currently have high failure rates such as those for Alzheimer’s and diabetes. In the last two decades companies like Foundation Medicine have used genomics to make an increasing impact on disease diagnostics in the Healthcare industry. We propose to similarly use genomics to make an impact on the pharmaceutical industry creating a “drug diagnostics” market in the process.

摘要随着表型筛选在药物发现中的回归，其主要问题是药物靶点识别。目前还没有很好的通用方法来对感兴趣的化合物进行目标识别。识别一种新药在分子水平上如何发挥作用对于改进它至关重要，这通常是使其发挥最佳作用所必需的。最终对患者安全有效的可能性。在这个提议中，我们展示了一个全基因组的 CRISPRi/一种在人类细胞中进行的筛选过程，可轻松识别目标药物的分子靶标。我们提出了初步证据，它也可以确定药物适应症的替代靶点，以及潜在的副作用靶点。我们证明了这种筛选过程可以应用于各种药物，疾病因此，它有潜力提高药物的数量，使它通过药物开发目前故障率很高的管道，如阿尔茨海默氏症和糖尿病管道。最近两几十年来，像基金会医学这样的公司已经利用基因组学对疾病产生了越来越大的影响。医疗保健行业的诊断。我们建议类似地使用基因组学来影响制药行业在此过程中创造了一个“药物诊断”市场。