IPF Drug Discovery Proof of Principle

描述(申请人提供)：活化的成纤维细胞是纤维化的关键介质，这些细胞既来自常驻细胞，也来自循环细胞，称为纤维细胞。纤维细胞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占成纤维细胞总数的很大比例，IPF是一种进行性和致命性的肺部疾病，目前尚无有效或特异的治疗方法。其他人利用纤维细胞直接计数来识别减少动物模型中纤维化发展的纤维细胞分化抑制物，然而这种方法不适用于高通量药物筛选。我们已经开发出一种简单可靠的方法来定量纤维细胞，可以用于识别针对纤维细胞发育和分化的药物，我们证明这使得针对这一病理生理靶点的小分子药物发现工作成为可能。这个第一阶段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)。进行HTS的能力将使我们能够在第二阶段确定一类新的特定抗纤维化药物来治疗IPF和相关疾病。这些药物将服务于尚未满足的临床需求，并可能降低与纤维化疾病相关的发病率和死亡率，并导致公共卫生状况的改善。此外，这些化合物还可以作为研究纤维细胞功能的有用的生物探针。 公共卫生相关性：纤维细胞是一种血细胞，参与各种进行性纤维化疾病，包括特发性肺纤维化(IPF)，这是一种致命的肺部疾病，目前尚无有效或特定的治疗方法。该应用程序旨在证明我们开发的方法将允许高通量筛选(HTS)。进行HTS的能力将使发现针对纤维细胞的药物成为可能。这些药物将服务于尚未得到满足的临床需求，并可能降低与纤维化疾病相关的发病率和死亡率，并导致公共卫生的改善。

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.