3D High Throughput Model to Predict Drug Efficacy in Fibrosis Progression vs Reversal

3D 高通量模型预测纤维化进展与逆转的药物疗效

基本信息

批准号：
9975675
负责人：
LOUISE HECKER
金额：
$ 23.5万
依托单位：
GEORGIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-15 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9975675
关键词：
3-Dimensional Accounting Affect Age Aging Apoptosis Biological Assay Biomedical Engineering Blood Vessels Cells Cellular Assay Cessation of life Cicatrix Collagen Contracts Development Disease Disease Progression Drug Combinations Drug usage Elderly Epidemic Exposure to FDA approved Fibroblasts Fibrosis Gel Heart Human Hydrogen Peroxide Individual Injury Kidney Liver Lung Lung diseases Modeling Monitor Myofibroblast Organ Oxidation-Reduction Pathologic Pathway interactions Patients Pharmaceutical Preparations Pharmacotherapy Phase Phenotype Pirfenidone Population Process Production Psychological reinforcement Quality of life Resistance Risk System Technology Testing Therapeutic age related aged aqueous base bioprinting body system clinically relevant cytokine drug candidate drug efficacy high throughput screening idiopathic pulmonary fibrosis improved inhibitor/antagonist novel pre-clinical preclinical development response screening senescence success therapeutic evaluation therapeutic target

项目摘要

ABSTRACT: 3D High Throughput Model to Predict Drug Efficacy in Fibrosis Progression vs Reversal Idiopathic pulmonary fibrosis (IPF) is the most relentlessly progressive and fatal fibrotic lung disorder, which disproportionately affects the elderly. Although two drugs have recently gained FDA-approval for IPF, these drugs only moderately slow the progression of lung decline and do not improve quality of life for patients. There are no available therapies that can `reverse' fibrosis. Despite efforts by numerous groups to develop IPF treatments, progress has been aggravatingly slow. This proposal focuses on two possible reasons for these difficulties: (1) Current pre-clinical screening models fail to reliably predict the success of drug candidates in humans, and (2) Although IPF is widely regarded as an age-related disease, drug treatments have not targeted age-associated pathologic mechanisms. The existing paradigm, that pathologic fibrosis is a “fibro-proliferative” process, has not led to effective IPF treatments. This proposal integrates expertise in fibroblast aging and novel IPF therapeutics in development (Hecker lab) with cutting edge technologies for microscale bioprinting and 3D cell assays (Takayama lab) to develop a high throughput phenotypic cellular screening assay to determine efficacy for fibrosis reversal. The proposed studies will utilize normal “control”, aged “senescent”, and IPF human lung fibroblasts in small numbers to bioengineer a high-throughput phenotypic assay that will evaluate fibrosis over a 21 day period. An aqueous two phase system (ATPS) bioprinting of these cells will be used to create microscale contraction assays that are several order of magnitude smaller in volume compared to conventional assays. Importantly, the project will repeatedly micro-print fresh collagen around already contracted cell-laden gels to enable repeated contractions over 21 days. The proposed model will enable the first high-throughput phenotypic screening assay with the capability to determine a drug candidate's efficacy for fibrosis progression and reversal. The new cellular assay will be validated for its ability to identify fibrosis reversal drugs using “Noxindoline” a highly selective Nox4 inhibitor that is currently in preclinical development by the Hecker lab. Noxindoline was identified by the Hecker lab through studies of age-dependent alterations in Nox4 that results in a sustained redox imbalance, and promotes senescence and apoptosis-resistance of myofibroblasts. The proposal hypothesizes that current therapies (Nintedanib and Pirfenidone) will inhibit the progression of pro-fibrotic phenotypes (but not reversal), whereas treatment with Noxindoline will promote the reversal of established pro-fibrotic phenotypes. The aims are: Aim1: Develop high throughput bioprinted cellular assay for fibrosis progression using non-senescent cells Aim2: Monitor fibrosis progression and reversal of senescent cells and IPF patient cells

摘要：3D高吞吐量模型，以预测纤维化进展中的药物功效与逆转特发性肺纤维化（IPF）是最遥远的进行性和致命纤维化肺部疾病，这是不成比例地影响了。尽管最近两种药物获得了IPF的FDA批准，但药物只会减慢肺下降的进展，并且不能改善患者的生活质量。没有可用的疗法可以“逆转”纤维化。尽管众多小组努力发展 IPF治疗，进展非常缓慢。该提议重点是两个可能的原因这些困难：（1）当前的临床前筛查模型无法可靠地预测药物的成功人类的候选人，（2）尽管IPF被广泛认为是与年龄有关的疾病，但药物治疗尚未针对与年龄相关的病理机制。现有的范式，该病理纤维化是一个“纤维增殖”过程，并未导致有效的IPF 治疗。该建议将成纤维细胞衰老和新型IPF疗法的专业知识整合到开发中（Hecker Lab）具有用于微观生物打印和3D细胞分析（Takayama Lab）的尖端技术开发高通量表型细胞筛选测定法，以确定纤维化逆转的效率。拟议的研究将利用正常的“控制”，老化的“感觉”和IPF人类肺成纤维细胞小。生物工程师的数量高通量表型测定法，该测定将在21天内评估纤维化。这些细胞的水性两相系统（ATP）生物打印将用于产生微观收缩与传统测定相比，体积小的几个数量级的测定顺序。重要的是，该项目将在已经含有含有细胞的细胞的凝胶周围反复微印新鲜胶原蛋白在21天内重复收缩。提出的模型将启用第一个高通量表型筛选分析的能力，可以确定候选药物的纤维化进展效率和逆转。新的细胞测定法将以使用其使用纤维化逆转药物的能力来验证 “ Noxindoline”是Hecker Lab目前正在临床前开发中的高度选择性NOX4抑制剂。 Hecker Lab通过研究NOX4中的年龄依赖性改变来确定Noxindoline 导致持续的氧化还原失衡，并促进肌纤维细胞。该提案假设当前的疗法（Nintedanib和Pirfenidone）将抑制促纤维化表型的进展（但不逆转），而Noxindoline的治疗将促进已建立的促纤维性表型的逆转。目的是： AIM1：开发高吞吐量生物打印的细胞测定，用于使用非渗透细胞进行纤维化进展 AIM2：监测纤维化的进展和感觉细胞和IPF患者细胞的反向