Drs. Bryan Roth and Gary Johnson receive 2 of 9 grants awarded by the NIH Illuminating the Druggable Genome Initiative which is supporting research to study 4 of the most commonly drug-targeted protein families
Dr. Bryan Roth and Dr. Gary Johnson have both received 3-year grants as part of a new NIH collaborative initiative, Illuminating the Druggable Genome (IDG). The goal of the initiative is to increase the understanding of the properties and function of poorly understood proteins within four of the most commonly drug-targeted protein families, the G-Protein coupled receptors (GPCRs), nuclear receptors (NRs), ion channels, and protein kinases. For the initial phase of the program, NIH has allocated $5.8 million to eight institutions and for intramural resources. The department of Pharmacology has received 2 of the 9 grants awarded.
Bryan Roth’s Award
Bryan Roth received a 3-year award of ~$400,000 per year to study Scalable technologies for illuminating the druggable GPCR-ome.
“DESCRIPTION: G-Protein Coupled Receptors (GPCRs) represent both the largest class of signaling receptors in the human genome and the family most targeted by therapeutic drugs. Responding to ligands that vary from protons to bioamines to lipids to chemokines, their attractiveness for drug discovery reflects the importance of the signals they transduce and, as has become apparent with the determination of their structures, the intrinsic ligand- ability of their binding sites. Despite intense interest, most GPCRs remain sparsely annotated by chemical matter. In this grant we will take a two-pronged approach to overcome these difficulties. In Specific Aim 1 we will develop and validate scalable assays in yeast and mammalian cells with which to screen a library of 5321 drugs and reagents. In Specific Aim 2 we will develop and validate scalable computational screens against modeled structures of the orphan GPCRs, leveraging the empirical hits. By the end of the project period we anticipate validating and executing physical screens against 30 orphan GPCRs and producing computationally optimized lead-like compounds for 20.” (~from NIH Report website, click on the link to learn more about this research project.)
Gary Johnson’s Award
Gary Johnson received a 3-year award of ~$400,000 per year to study Activation and Regulation of the Understudied Kinome Using MIB/MS Technology
“DESCRIPTION: A novel approach has been implemented to study the activation state of protein kinases “en masse”. Our methods allow isolation and analysis of protein kinases from cell lines, tissues and tumors assayed in a single mass spectrometry run using Multiplexed Inhibitor Beads (MIBs)….The aims will define comprehensive kinome activation signatures that include poorly or uncharacterized kinases. Aims include: 1. Determine the activation state of the kinome using MIB/MS for a series of human cell lines spanning different cancer types, human and mouse tumors, and normal tissues of the mouse. 2. Determine the response of the kinome to perturbation of cellular physiology using specific chemical probes targeting protein and lipid kinases, cytoskeleton, metabolic regulators, DNA damage and epigenetic chromatin modifying enzymes. 3. Determine the consequence of RNAi knockdown of understudied kinases on the activation state of the kinome. The aims emphasize determining the activation state of understudied kinases and if specific understudied kinases function as part of a signature of kinase activation/inhibition in response to specific cellular perturbations. This analysis will defne the signaling networks and cellular functions for which the activity of understudied kinases are regulated and contribute to homeostatic control mechanisms. The goal is to identify and validate which current understudied kinases function as regulatory nodes within the kinome and warrant future chemical probe development.” (~from NIH Report website, click on the link to learn more about this research project.)
More about the Illuminating the Druggable Genome (IDG) Program Initiative
This program will begin with a 3-year pilot phase. A primary component of this pilot is the establishment of a Knowledge Management Center designed to develop an integrated informatics solution that encompasses data accrual, analysis, data-driven prioritizations, and abstraction that will help identify gaps in knowledge of these proteins.
A complementary component of the Knowledge Management Center will support the development of a web portal to promote efficient and facile query and browsing tools that will bring together information from multiple data-sources
The second goal for the pilot phase will be to foster technology development. This will be focused on the adaptation of scalable assays and technologies to enable deep annotation of the Druggable Genome. The program will encourage approaches to probing the function of Druggable Genome.
Ultimately, the goal of the program is to foster basic research by accumulating genomic data to inform our knowledge of the proteome. Down the road, this will enable small businesses and the pharmaceutical industry with the ability to design novel therapeutics in increase human health.
The IDG is working closely with a complementary Common Fund effort, the Knockout Mouse Phenotyping (KOMP) program. The KOMP program builds upon prior efforts that generated genome-wide knockout mouse strains by conducting detailed phenotyping of many of the strains. By sharing information, IDG and KOMP will enhance the ability of both programs to prioritize genes of unknown function for study and the increase the pace and scientific depth of phenotyping studies, accelerating the discovery of new disease-relevant biology.
For more information on the KOMP program, see: http://commonfund.nih.gov/KOMP2/