Engineered Tissue Based Phenotypic Screening of Mixture based Libraries

基于工程组织的混合物库表型筛选

基本信息

批准号：
9145632
负责人：
Tetsuro Wakatsuki
金额：
$ 35万
依托单位：
INVIVOSCIENCES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-30 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9145632
关键词：
12 year old Adult Affinity Aging American Animal Model Biological Blast Cell Cardiac Cardiac Myocytes Cardiovascular Diseases Cells Chemicals Cicatrix Comb animal structure Complex Connective Tissue Contracts Data Degenerative polyarthritis Disease Disease model Dose Drug Targeting EFRAC Endothelial Cells Engineering Epidemic Evaluation Extracellular Matrix Extracellular Matrix Proteins FDA approved Fibroblasts Fibrosis Future Goals Government Hamman-Rich syndrome Health Heart Heart Hypertrophy Heart Injuries Heart failure Hospitalization Hour Human Hydrogels Hypertension Hypertrophy Individual Lead Left Libraries Mechanics Methods Modification Molecular Target Monitor Morphine Myocardial Myocardium Myofibroblast Patients Persons Pharmaceutical Preparations Pharmacologic Substance Phase Phenotype Physiological Piperazines Pirfenidone Play Positioning Attribute Preclinical Drug Evaluation Property Proteins Provider Pump Research Personnel Role Running Sampling Scanning Services Signal Pathway Smooth Muscle Myocytes Solid Staging Stem cells Sulfonamides System Systems Analysis Tars Technology Testing Time Tissue Engineering Tissues Toxic effect Training Transforming Growth Factor beta Wound Healing age related aged aging population base coronary fibrosis crosslink design drug candidate drug discovery effective therapy experience extracellular inhibitor/antagonist interstitial novel novel therapeutics phase 2 study reconstitution scaffold screening small molecule small molecule libraries tool wound

项目摘要

DESCRIPTION (provided by applicant): We propose to demonstrate the strength of combining our engineered tissue-based drug screening approach and a systematically organized mixture-based chemical library. This approach could become an ultimate tool to develop treatments for complex diseases, such as cardiac fibrosis, without known drug targets initially. Heart failure is the most common cause of hospitalization among Americans 65 or older. The heart failure with preserved ejection fraction (HFPEF) is becoming an epidemic among increasing population of aging Americans. Existence of activated fibroblasts, i.e. myofibroblasts, differentiated from fibroblasts, endothelial cells, and non-muscle cell is a hallmark of myocardium with HFPEF, and they stiffen myocardium to progress HFPEF. We developed a disease model for the human cardiac fibrosis using myofibroblast-containing engineered tissue constructs that recapitulate connective tissues of myocardium with fibrosis. Using our phenotypic screening system, we identified TPI-2049 (17,340 compound mixture) after analyzing a 42-scaffold scaffold ranking library (each scaffold sample contains mixtures of compounds), which is equivalent to screening >30 million compounds. While our final goal is to identify a novel drug for treating cardiac fibrosis, the proposed Phase I project will focus on performing a secondary sample screening of a compound mixture in the chemical scaffolds and identifying 50 individual compounds to pick 15 hit compounds to be tested and optimized in Phase II study. In a parallel study, we will analyze mechanisms of action of TPI-2049 in fibrosis relieving phenotypes and identify potential drug targets by performing affinity-free target identification method, stabilizing target molecules with individual hit compounds. Successful demonstration of combing engineered tissue based drug discovery system and scaffold ranking library with positional scanning technology will be extended to other drug discovery projects for age-related dieses such as osteoarthritis.

描述（由适用提供）：我们建议证明结合我们工程组织的药物筛查方法和系统组织混合物的化学库的强度。这种方法可能成为开发复杂疾病治疗的最终工具，例如心脏纤维化，最初没有已知的药物靶标。心力衰竭是65岁或以上的美国人住院的最常见原因。保留的射血分数（HFPEF）的心力衰竭正在成为越来越多的美国人人口的流行病。活化的成纤维细胞的存在，即肌纤维细胞，与成纤维细胞，内皮细胞和非肌肉细胞区别开来，是与HFPEF的心肌的标志，它们使心肌加强到HFPEF进行HFPEF。我们使用含有肌纤维细胞的工程组织构建体开发了一种用于人体心脏纤维化的疾病模型，该构建体概括了与纤维化的心肌相连的时机。使用表型筛选系统，我们在分析了42支脚架脚手架排名文库（每个脚手架样品中包含化合物的混合物）后，确定了TPI-2049（17,340种化合物混合物）（17,340种化合物混合物），这等效于筛选> 3000万种化合物。虽然我们的最终目标是确定一种用于治疗心脏纤维化的新药物，但拟议的I期项目将重点介绍化学支架中化合物混合物的二级样品筛选，并鉴定50种单独的化合物以在II期研究中进行测试和优化的15种命中化合物。在一项平行研究中，我们将分析TPI-2049在纤维化缓解表型中的作用机理，并通过执行无亲和力靶标识别方法来鉴定潜在的药物靶标，并用单个命中化合物稳定目标分子。通过位置扫描技术将梳理基于组织的药物发现系统和脚手架排名文库的成功证明将扩展到其他与年龄相关抑制剂（例如骨关节炎）的药物发现项目。