IPF Drug Discovery Proof of Principle

IPF 药物发现原理证明

• 批准号: 8057209
• 负责人: VICTOR E. BUCKWOLD
• 金额: $ 16.43万
• 依托单位: VERACITY BIOTECHNOLOGY, LLC
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2012-03-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8057209
• 关键词: Amyloid; Animal Model; Biological; Biological Assay; Biological Process; Blood Cells; Bone Marrow; Cell Count; Cells; Clinical; Development; Disease; Drug Delivery Systems; FDA approved; Fibroblasts; Fibrosis; Goals; Hamman-Rich syndrome; Impaired wound healing; In Vitro; Injection of therapeutic agent; Lead; Libraries; Lung diseases; Mediator of activation protein; Methods; Modeling; Morbidity - disease rate; Mus; Pathway interactions; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phase; Population; Preclinical Drug Evaluation; Proteins; Public Health; Pulmonary Fibrosis; Rattus; Research Personnel; Serum; Small Business Innovation Research Grant; Techniques; Variant; base; cell type; drug discovery; effective therapy; high throughput screening; in vivo; inhibitor/antagonist; innovation; mortality; small molecule

DESCRIPTION (provided by applicant): Activated fibroblasts are the key mediators of fibrosis and these cells are derived from both resident cells as well as from circulating cells termed fibrocytes. Fibrocytes are known to contribute significantly to the total population of fibroblasts in a variety of progressive fibrotic diseases including idiopathic pulmonary fibrosis (IPF), a progressive and fatal form of lung disease for which there are no effective or specific treatments. Others have utilized direct counting of fibrocytes to identify inhibitors of fibrocyte differentiation that reduce the development of fibrosis in animal models, however this method is not amenable to high-throughput drug screening. We have developed a simple and reliable method to quantify fibrocytes that can be used to identify drugs targeting fibrocyte development and differentiation and we demonstrate that this makes small molecule drug discovery efforts against this pathophysiologic target possible. The goal of this Phase I project is to show that our method can be used for high-throughput drug screening (HTS). The ability to undertake HTS will allow us to identify of a new class of specific antifibrotic drugs to treat IPF and related diseases during Phase II. These drugs will serve an unmet clinical need and could reduce the morbidity and mortality associated with fibrotic illnesses and lead to improvements in Public Health. In addition, these compounds may serve as useful biological probes of fibrocyte function. PUBLIC HEALTH RELEVANCE: Fibrocytes are a type of blood cells that are involved in a variety of progressive fibrotic diseases including idiopathic pulmonary fibrosis (IPF), a fatal form of lung disease for which there are no effective or specific treatments. This application aims to demonstrate that the methods that we have developed will allow for high throughput screening (HTS). The ability to undertake HTS will allow for the discovery of drugs targeting fibrocytes. These drugs will serve an unmet clinical need and could reduce the morbidity and mortality associated with fibrotic illnesses and lead to improvements in Public Health.

描述（由申请人提供）：活化的成纤维细胞是纤维化的关键介质，这些细胞来源于驻留细胞和称为纤维细胞的循环细胞。众所周知，在包括特发性肺纤维化（IPF）在内的各种进行性纤维化疾病中，纤维细胞在成纤维细胞总数中起着重要作用。特发性肺纤维化是一种进行性和致命的肺部疾病，目前尚无有效或特异性的治疗方法。其他人利用纤维细胞的直接计数来鉴定在动物模型中减少纤维化发展的纤维细胞分化抑制剂，然而这种方法不适合高通量药物筛选。我们已经开发了一种简单可靠的方法来量化纤维细胞，可用于识别靶向纤维细胞发育和分化的药物，我们证明这使得针对这种病理生理目标的小分子药物发现工作成为可能。这个I期项目的目标是证明我们的方法可以用于高通量药物筛选（HTS）。承担HTS的能力将使我们能够在II期确定一类新的特异性抗纤维化药物来治疗IPF和相关疾病。这些药物将满足未得到满足的临床需求，并可降低与纤维化疾病相关的发病率和死亡率，并改善公共卫生。此外，这些化合物可以作为纤维细胞功能的有用的生物探针。