权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Macrophage Phenotypic Modulators—A Novel Therapeutic Approach to Liver Fibrosis Treatment

巨噬细胞表型调节剂——肝纤维化治疗的新方法

基本信息

批准号：
10171770
负责人：
Bryan L Copple
金额：
$ 22.7万
依托单位：
MICHIGAN STATE UNIVERSITY
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：
2020-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10171770
关键词：
Affect Animal Model Antiviral Agents Biological Biological Assay Cause of Death Cells Cessation of life Chemicals Cirrhosis Clinical Research Development Disease Drug Screening Etiology Extracellular Matrix Fibrosis Gelatinases Gene Expression Goals Hepatic Stellate Cell Hepatitis C Image Immunofluorescence Immunologic Kupffer Cells Lead Libraries Liver Liver Cirrhosis Liver Fibrosis Matrix Metalloproteinases Measures Mediator of activation protein Messenger RNA Methods Mus Patients Pharmaceutical Preparations Pharmacological Treatment Phenotype Population Prevalence Process Production Property Proteins Resolution antifibrotic treatment cell type collagenase drug candidate drug repurposing follow-up high risk high throughput screening macrophage nano-string new therapeutic target novel novel strategies novel therapeutic intervention novel therapeutics phenotypic biomarker screening selective expression small molecule libraries therapeutically effective

项目摘要

Project Summary Liver fibrosis/cirrhosis is the 14th leading cause of death worldwide. Despite the prevalence of this disease, there are no drugs to treat liver fibrosis/cirrhosis. Several landmark clinical studies have demonstrated that fibrosis, and even cirrhosis, are reversible in patients. In animal models, during regression of fibrosis, disease causing, “pro-fibrotic macrophages” differentiate into “pro-resolving macrophages”. These macrophages produce matrix metalloproteinases (MMPs) that remove excess extracellular matrix and produce mediators that terminate matrix production by “activated” hepatic stellate cells, the primary matrix producing cell in the liver. The studies proposed in this application aim to exploit the phenotypic plasticity of pro-fibrotic macrophages and identify chemicals/drugs that stimulate their conversion into pro-resolving macrophages. Towards this goal, we have developed a primary screening assay that utilizes high-content imaging to detect macrophage phenotypic transition in a 384 well format. With this assay, we propose to screen a library of 3,000 compounds of known mechanism of action to identify drugs for repurposing as macrophage phenotypic modulators with anti-fibrotic properties. We will screen an additional library of 23,000 compounds with unknown activities to identify novel anti-fibrotics. Positive hits from these screens will be further characterized by using the Nanostring assay, in a medium throughput format, to quantify several macrophage phenotype- specific mRNAs. Top hits from this secondary screen will be further evaluated in biological assays for anti- fibrotic activity. Collectively, these studies have the potential to identify novel anti-fibrotics that not only limit further fibrosis development but stimulate fibrosis reversal by triggering the conversion of pro-fibrotic macrophages into pro-resolving macrophages. Identification of compounds with this novel activity has the potential to tremendously impact treatment of liver fibrosis/cirrhosis.

项目总结