This is a proposal to continue the Cystic Fibrosis (CF) Research and Translation Center at the University of California, San Francisco and collaborating institutions. The focus of our Center remains the discovery and advancement of novel small-molecule therapies for CF. The original proposal 15 years ago 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. The proposed Center will fund four scientific Cores and an administrative Core to support the activities of 2 Pilot Projects and at least 22 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), Assays & Cell Models (Core B, Peter Haggie, Director), Chemistry (Core C, Mark Kurth (UC Davis) and Marc Anderson (San Francisco State University), co-Directors), and Animal Pharmacology & Models (Core D, Onur Cil, Director). Major focuses of projects utilizing the Cores include development of therapies for the `remaining 10%' of CF subjects that are not benefitted by available CFTR modulators, which include tailored modulators for rare and difficult-to-treat CFTR mutants, and mutation- agnostic therapies such as SLC26A4 (pendrin) inhibitors and SLC26A9 modulators; and therapies targeting gastrointestinal and renal complications of CF, such as SLC26A3 (DRA) inhibitors for CF constipation and enteric hyperoxaluria, and SLC26A6 (PAT-1) inhibitors for CF constipation and meconium ileus. The goal of the research to be enhanced by the Center remains the development of novel small-molecule therapies for CF that can be translated into the clinic.
The central objective of the UCSF P30 CF Research and Translation Center is the discovery of new targets and drugs to treat cystic fibrosis (CF). There are four Cores: High-Throughput Screening, Assays & Cell Models, Chemistry, and Animal Pharmacology & Models, which support the activities of 2 pilots and at least 22 CF-related projects. Major themes of the Center are development of therapies for the `remaining 10%' of CF subjects that are not benefitted by available CFTR modulators, and development of therapies targeting gastrointestinal and renal CF manifestations by modulating ion transporters other than CFTR.
|Lee, Sujin; Cil, Onur; Diez-Cecilia, Elena et al. (2018) Nanomolar-Potency 1,2,4-Triazoloquinoxaline Inhibitors of the Kidney Urea Transporter UT-A1. J Med Chem 61:3209-3217|
|Tradtrantip, Lukmanee; Felix, Christian M; Spirig, Rolf et al. (2018) Recombinant IgG1 Fc hexamers block cytotoxicity and pathological changes in experimental in vitro and rat models of neuromyelitis optica. Neuropharmacology 133:345-353|
|Phuan, Puay-Wah; Veit, Guido; Tan, Joseph-Anthony et al. (2018) ?F508-CFTR Modulator Screen Based on Cell Surface Targeting of a Chimeric Nucleotide Binding Domain 1 Reporter. SLAS Discov 23:823-831|
|Verkman, Alan S; Yao, Xiaoming; Smith, Alex J (2018) The evolving mystery of why skeletal muscle is spared in seropositive neuromyelitis optica. J Cell Mol Med 22:2039-2040|
|Sun, Dingyuan I; Tasca, Alexia; Haas, Maximilian et al. (2018) Na+/H+ Exchangers Are Required for the Development and Function of Vertebrate Mucociliary Epithelia. Cells Tissues Organs :1-14|
|Bhakta, Nirav R; Christenson, Stephanie A; Nerella, Srilaxmi et al. (2018) IFN-stimulated Gene Expression, Type 2 Inflammation, and Endoplasmic Reticulum Stress in Asthma. Am J Respir Crit Care Med 197:313-324|
|Smith, Alex J; Verkman, Alan S (2018) The ""glymphatic"" mechanism for solute clearance in Alzheimer's disease: game changer or unproven speculation? FASEB J 32:543-551|
|Duan, Tianjiao; Smith, Alex J; Verkman, Alan S (2018) Complement-dependent bystander injury to neurons in AQP4-IgG seropositive neuromyelitis optica. J Neuroinflammation 15:294|
|Verkman, Alan S; Smith, Alex J; Phuan, Puay-Wah et al. (2017) The aquaporin-4 water channel as a potential drug target in neurological disorders. Expert Opin Ther Targets 21:1161-1170|
|Zhu, Jie S; Son, Jung-Ho; Teuthorn, Andrew P et al. (2017) Diverting Reactive Intermediates Toward Unusual Chemistry: Unexpected Anthranil Products from Davis-Beirut Reaction. J Org Chem 82:10875-10882|
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