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.

项目概要肝纤维化/肝硬化是全球第 14 大死亡原因，尽管这种疾病很普遍。没有药物可以治疗肝纤维化/肝硬化，几项具有里程碑意义的临床研究表明。在动物模型中，纤维化、甚至肝硬化在纤维化、疾病消退期间是可逆的。导致“促纤维化巨噬细胞”分化为“促分解巨噬细胞”。产生基质金属蛋白酶 (MMP)，去除多余的细胞外基质并产生介质终止“激活的”肝星状细胞的基质生产，肝星状细胞是肝星状细胞中的主要基质生产细胞本申请提出的研究旨在开发促纤维化的表型可塑性。巨噬细胞并识别刺激其转化为促解析巨噬细胞的化学物质/药物。为了实现这一目标，我们开发了一种初级筛选方法，利用高内涵成像来检测通过此测定，我们建议筛选 3,000 个巨噬细胞表型转变。已知作用机制的化合物，用于鉴定用于重新利用巨噬细胞表型的药物我们将筛选具有抗纤维化特性的额外库，其中包含 23,000 种化合物。鉴定新型抗纤维化的未知活性将被进一步表征。通过使用中等通量格式的纳米线测定来量化几种巨噬细胞表型- 来自第二次筛选的特定 mRNA 将在抗-生物测定中得到进一步评估。总的来说，这些研究有可能鉴定出不仅限制纤维化的新型抗纤维化药物。进一步纤维化发展，但通过触发促纤维化的转化来刺激纤维化逆转具有这种新活性的化合物的鉴定具有以下意义：可能对肝纤维化/肝硬化的治疗产生巨大影响。