Exploiting emerging ideas in G protein-coupled receptor biology and pharmacology to treat asthma

Thomas Jefferson University, Philadelphia PA

Investigators

Abstract

Overall Program Abstract For this NHLBI PPG we have assembled a highly collaborative team of experts in G protein-coupled receptor (GPCR) biology, airway smooth muscle (ASM) biology, and asthma biology to pursue the theme of “exploiting emerging ideas in G protein-coupled receptor biology and pharmacology to treat asthma.” The Program expects to achieve the following goals: 1) Identify novel targets and targeting molecules involving GPCR regulation of ASM contraction and proliferation; 2) Delineate the mechanisms by which these novel targets/targeting molecules regulate these ASM functions; and 3) Establish the therapeutic utility of novel targeting molecules in in vivo models of asthma. These goals will be accomplished across 4 scientific projects, two scientific cores, and an administrative core, to test the central hypothesis that novel modes of GPCR regulation can be targeted to effect superior management of ASM function and asthma. Each project takes advantage of a robust experimental strategy that incorporates multiple cell, tissue, and in vivo models of ASM function, complemented by cutting-edge biochemical analyses to detail mechanisms of action. Project 1 will test the ability of, and mechanisms effected by, recently-developed biased β2AR ligands to manage ASM contractility and the asthma phenotype, while (with Core A) leveraging recent insight in β2AR structure-activity relationship to develop new ligands superior to in-hand leads. Project 2 pivots away from the receptor locus as a means to regulate GPCR control of ASM, to explore the role of the cAMP transport inhibitor ABBC1, positing that ABBC1- dependent pathways inhibit β-agonist effects on HASM E-C coupling, and are upregulated in asthma patients. Project 3 similarly explores regulation of downstream Gq-coupled receptor signaling by diacylglycerol kinase (DGK), whose targeting effectively inhibits pro-contractile and pro-mitogenic GPCR signaling in ASM to control the asthma phenotype. Project 4 breaks new ground in the exploration of Class C GPCRs, clarifying the roles of GPRC5A and GPRC5B in ASM and asthma biology, and in collaboration with Core A, developing new ligands to skew the signaling competition between these 2 receptors towards therapeutically beneficial GPRC5A signaling and away from pathogenic GPRC5B signaling. The four projects will be supported by Core A, which will employ high-throughput screening of diverse libraries of arrayed and expressed small molecules, and further employ structural biology, computational modeling and virtual screening to leverage screening results, predict and test novel drug-like molecules. Core B will provide all de-identified human cell and tissue models to study novel mechanisms regulating EC coupling in HASM. Core C will provide administrative support for the program. Each project also collaborates with other projects to test combination strategies that target receptors (β2AR, GPR5A, GPR5B) in conjunction with downstream regulators (ABCC1, DGK). The strengths of this Program are the common focus on a single theme and the productive working relationship among investigators with the ability to apply cutting-edge GPCR biology to key questions in asthma biology and pharmacology.