Novel small-molecule therapies for CF

总体描述（由申请人提供）：这是一份继续我们在加州大学旧金山弗朗西斯科和合作机构的囊性纤维化（CF）研究和转化核心中心的提案。我们核心中心的重点仍然是发现和评估CF的新型小分子疗法。最初的建议是在Verkman博士和合作者的实验室建立了一个独特的学术药物发现计划，以识别和表征CFTR活性的小分子调节剂。拟议的核心中心将资助五个核心，以支持两个试点项目和28个与气候变化有关的项目的活动。核心主任是经验丰富的CF调查员，在其调查领域具有公认的专业知识和富有成效的合作历史。核心包括：高通量筛选（核心A，Alan Verkman，主任），临床资源（核心B，Dennis Nielson，主任），细胞模型（核心C，Walter Finkbeiner，主任），合成化学（核心D，Mark Kurth，主任），细胞和组织生物测定（核心E，Peter Haggie，主任）。利用核心的项目包括发现上皮离子转运蛋白（CFTR，CaCC，ENaC，NKCC，钾通道），上皮细胞粘蛋白分泌和假单胞菌生物膜形成的调节剂。利用这些核心的其他项目包括对CF中肺部疾病机制的研究。核心中心加强研究的总目标是开发新的 CF的小分子疗法，可以转化为临床。

DESCRIPTION, OVERALL (provided by applicant): This is a proposal to continue our Cystic Fibrosis (CF) Research and Translational Core Center at the University of California, San Francisco and collaborating institutions. The focus of our Core Center remains the discovery and evaluation of novel small-molecule therapies for CF. The original proposal followed from 5 years of work establishing a unique academic drug discovery program in the laboratories of Dr. Verkman and collaborators to identify and characterize small-molecule modulators of CFTR activity. The proposed Core Center will fund five Cores to support the activities of 2 Pilot Projects and 28 CF-related projects. The Core directors are experienced CF investigators with recognized expertise in their areas of investigation and a history of productive collaboration. The Cores include: High-Throughput Screening (Core A, Alan Verkman, director), Clinical Resources (Core B, Dennis Nielson, director), Cell Models (Core C, Walter Finkbeiner, director), Synthetic Chemistry (Core D, Mark Kurth, director), and Cell & Tissue Bioassays (Core E, Peter Haggie, director). Projects to utilize the cores include the discovery of modulators of epithelial ion transporters (CFTR, CaCCs, ENaC, NKCC, potassium channels), epithelial cell mucin secretion, and Pseudomonas biofilm formation. Other projects to utilize the cores include research on mechanisms of lung disease in CF. The general goal of the research to be enhanced by the Core Center is to develop new small-molecule therapies for CF that can be translated into the clinic.