Macrophage Phenotypic Modulators—A Novel Therapeutic Approach to Liver Fibrosis Treatment
Macrophage Phenotypic Modulators—A Novel Therapeutic Approach to Liver Fibrosis Treatment
批准号:
10171770
负责人:
Bryan L Copple
金额:
$22.7万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
已结题
起止时间:
2020-06-01 至 2024-05-31
关键词:
AffectAnimal ModelAntiviral AgentsBiologicalBiological AssayCause of DeathCellsCessation of lifeChemicalsCirrhosisClinical ResearchDevelopmentDiseaseDrug ScreeningEtiologyExtracellular MatrixFibrosisGelatinasesGene ExpressionGoalsHepatic Stellate CellHepatitis CImageImmunofluorescence ImmunologicKupffer CellsLeadLibrariesLiverLiver CirrhosisLiver FibrosisMatrix MetalloproteinasesMeasuresMediator of activation proteinMessenger RNAMethodsMusPatientsPharmaceutical PreparationsPharmacological TreatmentPhenotypePopulationPrevalenceProcessProductionPropertyProteinsResolutionantifibrotic treatmentcell typecollagenasedrug candidatedrug repurposingfollow-uphigh riskhigh throughput screeningmacrophagenano-stringnew therapeutic targetnovelnovel strategiesnovel therapeutic interventionnovel therapeuticsphenotypic biomarkerscreeningselective expressionsmall molecule librariestherapeutically effective
中文摘要
项目摘要
肝纤维化/肝硬变是全球第14大主要死亡原因。尽管这种疾病很流行,
目前还没有治疗肝纤维化/肝硬变的药物。几项里程碑式的临床研究已经证明
纤维化,甚至是肝硬变,在患者中是可逆的。在动物模型中,在纤维化消退期间,疾病
导致“促纤维化巨噬细胞”分化为“促分解巨噬细胞”。这些巨噬细胞
产生基质金属蛋白酶(MMPs),清除多余的细胞外基质并产生介质
通过“激活”的肝星状细胞终止基质的产生,肝星状细胞是肝脏中主要的基质产生细胞。
肝脏。本申请中提出的研究旨在开发促纤维化的表型可塑性。
并找出刺激巨噬细胞转化为支持分解的巨噬细胞的化学物质/药物。
为了实现这一目标,我们开发了一种利用高含量成像来检测
巨噬细胞表型转变为384孔型。通过这项测试,我们建议筛选一个拥有3000人的文库
识别作为巨噬细胞表型再利用药物的已知作用机制的化合物
具有抗纤维化特性的调节剂。我们将再筛选一个包含23,000个化合物的文库
识别新型抗纤维化药物的未知活性。来自这些屏幕的积极点击将被进一步描述
通过使用纳米串分析,以中等吞吐量的形式,量化几种巨噬细胞表型-
特定的mRNAs。来自二次筛查的最高命中率将在生物检测中进一步评估抗-
纤维化活跃性。总的来说,这些研究有可能发现新型的抗纤维化药物,这些药物不仅可以限制
进一步的纤维化发展,但通过触发前纤维化的转化来刺激纤维化逆转
巨噬细胞转化为支持分解的巨噬细胞。具有这种新活性的化合物的鉴定具有
有可能对肝纤维化/肝硬变的治疗产生巨大影响。
英文摘要
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.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Novel proteolytic mechanisms driving pathologic hepatic congestion in drug-induced hepatotoxicity
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批准号:10638320
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项目类别:
-
资助金额:$49.79万
-
财政年份:2023
-
负责人:Bryan L Copple
-
依托单位:
COBRE: U OF KANSAS MEDICAL CTR: HISTOLOGY/PHENOTYPING CORE
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批准号:8360782
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项目类别:
-
资助金额:$3.79万
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财政年份:2011
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负责人:Bryan L Copple
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依托单位:
COBRE: U OF KANSAS MEDICAL CTR: HISTOLOGY/PHENOTYPING CORE
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批准号:8167661
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项目类别:
-
资助金额:$3.56万
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财政年份:2010
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负责人:Bryan L Copple
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依托单位:
COBRE: U OF KANSAS MEDICAL CTR: CORE D: HISTOLOGY/PHENOTYPING CORE
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批准号:7959505
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项目类别:
-
资助金额:$3.65万
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财政年份:2009
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负责人:Bryan L Copple
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依托单位:
COBRE: U OF KANSAS MEDICAL CTR: CORE D: HISTOLOGY/PHENOTYPING CORE
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批准号:7720182
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项目类别:
-
资助金额:$3.31万
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财政年份:2008
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负责人:Bryan L Copple
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依托单位:
Role of Early Growth Response Factor-1 in Cholestatic Liver Injury
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批准号:7484469
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项目类别:
-
资助金额:$8.23万
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财政年份:2007
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负责人:Bryan L Copple
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依托单位:
Role of Early Growth Response Factor-1 in Cholestatic Liver Injury
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批准号:8371762
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项目类别:
-
资助金额:$19.85万
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财政年份:2007
-
负责人:Bryan L Copple
-
依托单位:
Role of Early Growth Response Factor-1 in Cholestatic Liver Injury
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批准号:7387478
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项目类别:
-
资助金额:$29.53万
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财政年份:2007
-
负责人:Bryan L Copple
-
依托单位:
Role of Early Growth Response Factor-1 in Cholestatic Liver Injury
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批准号:7259929
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项目类别:
-
资助金额:$30.14万
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财政年份:2007
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负责人:Bryan L Copple
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依托单位:
PROJ 4: PHYSIOLOGICAL FUNCTION OF NUCLEAR RECEPTORS IN CHOLESTATIC LIVER DISEASE
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批准号:7610775
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项目类别:
-
资助金额:$22.65万
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财政年份:2007
-
负责人:Bryan L Copple
-
依托单位:
Role of Early Growth Response Factor-1 in Cholestatic Liver Injury
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批准号:7617269
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项目类别:
-
资助金额:$29.53万
-
财政年份:2007
-
负责人:Bryan L Copple
-
依托单位:
Role of Early Growth Response Factor-1 in Cholestatic Liver Injury
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批准号:7771502
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项目类别:
-
资助金额:$0.15万
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财政年份:2007
-
负责人:Bryan L Copple
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依托单位:
Role of Early Growth Response Factor-1 in Cholestatic Liver Injury
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批准号:8062001
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项目类别:
-
资助金额:$11.72万
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财政年份:2007
-
负责人:Bryan L Copple
-
依托单位:
COBRE: U OF KANSAS MEDICAL CTR: CORE D: HISTOLOGY/PHENOTYPING CORE
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批准号:7610770
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项目类别:
-
资助金额:$11.92万
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财政年份:2007
-
负责人:Bryan L Copple
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依托单位:
PROJ 4: PHYSIOLOGICAL FUNCTION OF NUCLEAR RECEPTORSIN CHOLESTATIC LIVER DIS
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批准号:7382254
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项目类别:
-
资助金额:$16.35万
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财政年份:2006
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负责人:Bryan L Copple
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依托单位:
THROMBIN AND INFLAMMATORY TISSUE INJURY
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批准号:6164606
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项目类别:
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资助金额:$3.75万
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财政年份:2000
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负责人:Bryan L Copple
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依托单位:
THROMBIN AND INFLAMMATORY TISSUE INJURY
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批准号:2862826
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项目类别:
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资助金额:$3.17万
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财政年份:1999
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负责人:Bryan L Copple
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依托单位:
海外基金