Second Face to Face meeting of GLUE Grant planning group.
University of Pennsylvania, April 16th, 2009.
The group discussed ways in which we could integrate our proposals across the translational divide that demonstrated the amplification of new knowledge derived from formation of the consortium and that was consistently innovative.
Several ARRA responses may support initial elements of the GLUE consortium. These include proposals
• to perform studies in mice and humans to determine whether heterogeneity of COX-2 expression in EBV transformed lymphocytes ex vivo is related to
variability in NSAID response;
• to determine genetic modifiers of the hypertensive response to NSAIDs involving studies in inbred mice and humans and the development of a related systems network;
• to utilize novel mouse models to explore the mechanism by which NSAIDs predispose to heart failure;
• limited studies in humans to explore potential variability in analgesic efficacy of NSAIDs.
These topics were discussed at the meeting. Ethnic variability in enzyme expression prompted commentary on some evidence that this may exist also for efficacy and CV risk. It was suggested to develop a matrix of relevant quantitative variables (and evocative stimuli) relevant to NSAID response indicating their tractability in yeast, mammalian cells, fish, mice and humans.
The variables considered were;
Blood pressure (salt loading/deprivation; pressor infusion)
Renal function (GFR, urine biomarkers, osmolarity etc)
Analgesic response (self rated VAS, fMRI, arterial spin labeling estimate of blood flow)
Potential PET readouts
Drug and metabolite exposure
Hepatic function (enzymes)
GI – Hgb in zebrafish
Markers of on target action (urine metabolites, whole blood assays)
Markers of off target action ( lipidomics [PL turnover, Fatty acyl CoA synthase
], proteomics, metabolomics)
There was some discussion of approaches to elucidating variability in drug response at the single cell level in yeast, fish and mammalian cells; the determination of how confluence might influence this variability and the recapitulation of phenotype by gene restoration at the single cell level by RNA injection.
Factors relevant to mining analgesic efficacy were discussed including the variable models (CFA, carigeenan) in mice or in humans (dental vs arthritic pain). There is a particular interest in trying to model factors that determine acute to chronic pain transition, the potential role of astrocytes and whether these are variably impacted by NSAIDs.
A HTS behavioral company was mentioned that can quantitatively assess >100 behaviors.
The next meeting will be with a group ( Kohane, Altmann, Wishart, Iyengar, Hogenesch, Blair and FitzGerald) focused on informatics [ June 8th]. It was felt desirable that we would structure access at two levels (i) preliminary data access to all working groups within the consortium and (ii) open access when data are finalized.
Emphasis should be placed on a structured approach to project management.
It was felt that novel contributions of this consortium could include the development of systems approaches to using multiple drugs against multiple targets. The engagement of the FDA would be a unique strength of the proposal. Amongst our outputs would be
• new quantitiative models of drug response ;
• new technologies;
• new ideas about how drugs might be developed and approved;
• new exposures for trainees.
It was felt that we should emphasize the movement of trainees amongst the groups to gain multidisciplinary exposure in this arena.
New candidates for inclusion in the network were mentioned.
A suggestion from Colin was to include Regeneron and their Velocimouse technology. Perhaps they could generate a series of human/mouse chimeras
taking large human BAC clones of chromosome 1 (about 200 kb) represented in the immortalized lymphocyte populations of various COX-2 expressors from different ethnic populations and make mice with variable COX-2 expression (mated to COX-2 KO mice).
This may allow us to test for some specific genetic components to the equation.
There was high enthusiasm for trying to persuade David Botstein within the consortium.