The Hepato/Renal Fibrocystic Diseases Therapeutic and Screening Resource: Core D

项目摘要 没有FDA批准的治疗任何形式的HRFD的方法。然而，分子途径高度相关， 最近已经鉴定了几种特定HRFD的病理生物学。这给药理学带来了希望， 靶向这些途径的可药物化组分可减弱HRFD进展。由于类似水平的 疾病知识触发了FDA批准的用于其它遗传性疾病的治疗的鉴定（例如， 囊性纤维化），我们相信至少某些形式的HRFD可以获得相当的成功。帮助 为了实现这一目标，我们建立了治疗药物开发和筛选资源（核心D）， 提供必要的工具、模型和技术，并沿着一个用于铅化合物的综合计划 优化和临床前开发。 具体而言，（i）解决缺乏可用于鉴定和表征 HRFD先导化合物，核心D将开发一种用于先导化合物鉴定的易处理模型， 具有已知HRFD突变的良好表征的细胞系组。这种基于小区的资源与 HRFD相关报告基因检测为识别HRFD先导化合物提供了创新和强大的工具 以及用于表征可能被单一药物靶向的功能性HRFD蛋白结构域。（二） 为了改善药物疗效的评估，核心D将开发体内预测模型， 使用已建立和新开发的标志物纵向监测动物HRFD模型中的药物作用 疾病的发展。(iii)为了加强优先药物的临床前安全性评估，核心D将 开发针对HRFD的毒理学和安全性筛查。 综上所述，为了推进HRFD治疗药物的开发，核心D将建立创新药物 发现和标准化的药物疗效筛选系统。这些新开发的资源将成为 可供HRFD核心中心研究者基地使用，以推进新HRFD的发现和评估 治疗学此外，HRFD模型中药物疗效测试的标准化策略将有助于巩固 通过提供特异性HRFD进展调节的成本效益体内评价， 方面的影响.因此，我们预计核心D也将通过以下方式间接促进HRFD疗法的发展： 通过提高HRFD赠款和手稿的质量， 吸引新的非人力资源开发调查人员进入这一领域。

PROJECT SUMMARY There is no FDA-approved therapy for any form of HRFDs. However, molecular pathways highly relevant to pathobiology of several specific HRFD have recently been identified. This raises hope that pharmacological targeting of druggable components of these pathways may attenuate HRFD progression. Since similar level of disease knowledge triggered identification of FDA-approved treatments for other inherited disorders (e.g., cystic fibrosis), we believe that comparable success can be achieved for at least some forms of HRFD. To help facilitate this goal, we have established the Therapeutics Development and Screening Resource (Core D) to provide essential tools, models and technologies, along with an integrated plan for their use in lead compound optimization and preclinical development. Specifically, (i) to address lack of predictive in vitro assays that can be used to identify and characterize HRFD lead compounds, Core D will develop a tractable model for lead compound identification consisting of a well characterized panel of cell lines with known HRFD mutations. Coupling of such cell-based resource with HRFD relevant reporter assays offers innovative and robust tool for identification of HRFD lead compounds and for characterization of functional HRFD protein domains that are potentially targeted with a single drug. (ii) To improve assessment of drug efficacy, Core D will develop in vivo predictive models for standardized longitudinal monitoring of drug effects in animal HRFD models using established and newly developed markers of the disease progression. (iii) To enhance preclinical safety assessment of prioritized drugs, Core D will develop HRFD-specific toxicology and safety screens. In summary, to advance development of HRFD therapeutics, Core D will establish innovative drug discovery and standardized drug efficacy screening systems. These newly developed resources will be made available to the HRFD Core Center Investigator Base to advance discovery and evaluation of new HRFD therapeutics. In addition, a standardized strategy for drug efficacy testing in HRFD models will help to solidify emerging hypotheses by providing cost-effective in vivo evaluation of specific HRFD progression modulating effects. Therefore, we anticipate that Core D will also catalyze development of HRFD therapeutics indirectly by attracting additional funding to HRFD research by enhancing quality of HRFD grants and manuscripts and by attracting new non-HRFD investigators to this field.