Herr Prof. Dr. med. Tilo Grosser

We are studying the translational therapeutics of lipid mediators in the eicosanoid biosynthetic-response pathway. Most cells in the organism have the capacity to form eicosanoids, which have important regulatory functions in many physiological and pathological processes. Nonsteroidal anti-inflammatory drugs (NSAIDs) exert their analgesic and anti-inflammatory effects via inhibition of eicosanoid formation. NSAIDs are amongst the most commonly consumed drugs and their use has been associated with cardiovascular events, including myocardial infarction and stroke, hypertension, heart failure and sudden cardiac death (for review 1, 2, 3).

My group is interested in understanding how the benefit of these drugs can be exploited while managing or avoiding their adverse effects. If this can be established for NSAIDs, where there is a subtle trade-off between benefit and risk at the population level (but perhaps less subtle at the individual level), it may serve as a general paradigm for the progressive personalization of other classes of drugs commonly used in chronic disease. We investigate mechanisms of variability in the response to NSAIDs with a focus on cardiovascular effects and inflammatory pain.

Variability in the cardiovascular response to NSAIDs
In a series of studies, we provided proof-of-concept to show that it might be possible to predict a patient’s response to NSAIDs based on biomarkers of COX activity (4). We observed that the prevalence of a mechanistically consistent, stable, and specific phenotype of true pharmacological resistance to aspirin – such as might be explained by genetic causes is extremely rare (5). We developed the first quantitative, direct assay of aspirin action on platelet COX-1 and using this biomarker, we demonstrated directly the drug-drug-interaction with aspirin of ibuprofen and naproxen but not celecoxib, consistent with the absence of COX-2 from human platelets (6). These data have provided the rationale for ongoing research into genetic and non-genetic sources of variation in response to NSAIDs (NCT02502006).

Inflammatory pain
There is an urgent need for improving non-addictive pain relief strategies (7). NSAIDs represent an important non-addictive option (8), but there is substantial heterogeneity in analgesic response (9). We have investigated the variability in analgesic response to ibuprofen using a model of acute surgical pain (third molar extraction). While ibuprofen on average relieved third molar extraction pain, analgesic efficacy was variable among individuals, and the need for opioid rescue medication was associated with molecular indices of COX inhibition (10). This has served as a foundation for ongoing work exploring the mechanisms that contribute to variability in pain relief with NSAIDs in clinical trials (NCT03893175) and in model organisms (bioRxiv). As collaborators of research groups at the University of Pennsylvania we are exploring the potential of nano therapeutics approaches to provide relief from inflammation (11, 12).

Systems pharmacology
I have a long standing interest in advancing systems approaches in pharmacology. For example, we developed a computational method to enable integrated analysis of large-scale mass spectrometric proteomics studies, which became the basis for many similar software tools currently in use (13). Using this tool we profiled the dynamics of protein expression during early zebrafish development resulting in the most rigorous protein expression study in this model organism at the time (14) and analyzed the platelet sheddome (15). I contributed to the development of new methods to network based analysis of GWAS (16) and to the analysis of circadian rhythms (17). Ongoing collaborative work focuses on differential expression analyses of RNAseq analyses (bioRxiv).

A detour into public health during the pandemic
During the pandemic I served on our children’s school’s COVID-19 Scientific Advisory Committee in Philadelphia. Following the mandatory closure of all schools in Philadelphia throughout Spring 2020, we began to develop a plan for in-person learning after the summer break in September. As there was no guidance for schools from the U.S. health agencies at the time we started working on the re-opening plan, we collaborated with colleagues at the University of Pennsylvania to develop a robust layered mitigation approach. We published our concept in an editorial in Science (18) followed by a more detailed review of evidence based COVID-19 mitigation in schools (19).

2. Grosser T, Yu Y, FitzGerald GA. Emotion recollected in tranquility: lessons learned from the COX-2 saga. Annu Rev Med. 2010;61:17-33.

3. Grosser T, Ricciotti E, FitzGerald GA. The Cardiovascular Pharmacology of Nonsteroidal Anti-Inflammatory Drugs. Trends Pharmacol Sci. 2017;38:733-748.

4. Fries S*, Grosser T*, Price TS, Lawson JA, Kapoor S, DeMarco S, Pletcher MT, Wiltshire T, FitzGerald GA. Marked interindividual variability in the response to selective inhibitors of cyclooxygenase-2. Gastroenterology. 2006;130:55-64. *) equal contribution

5. Grosser T*, Fries S*, Lawson JA, Kapoor SC, Grant GR, FitzGerald GA. Drug resistance and pseudoresistance: an unintended consequence of enteric coating aspirin. Circulation. 2013;127(3):377-85. *) equal contribution

6. Li X, Fries S, Li R, Lawson JA, Propert KJ, Diamond SL, Blair IA, FitzGerald GA, Grosser T. Differential impairment of aspirin-dependent platelet cyclooxygenase acetylation by nonsteroidal antiinflammatory drugs. Proc Natl Acad Sci U S A. 2014;111:16830-5.

7. Grosser T, Woolf CJ, FitzGerald GA. Time for nonaddictive relief of pain. Science. 2017;355(6329):1026-1027.

8. Grosser T, Theken KN, FitzGerald GA. Cyclooxygenase Inhibition: Pain, Inflammation, and the Cardiovascular System. Clin Pharmacol Ther.;102(4):611-622.

9. Theken KN, Lee CR, Gong L, Caudle KE, Formea CM, Gaedigk A, Klein TE, Agúndez JAG, Grosser T. Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC) for CYP2C9 and Nonsteroidal Anti-Inflammatory Drugs. Clin Pharmacol Ther. 2020;108(2):191-200.

10. Theken KN, Hersh EV, Lahens NF, Lee HM, Li X, Granquist EJ, Giannakopoulos HE, Levin LM, Secreto SA, Grant GR, Detre JA, FitzGerald GA, Grosser T*, Farrar JT*. Variability in the analgesic response to ibuprofen is associated with cyclooxygenase activation in inflammatory pain. Clin Pharmacol Ther. 2019;106:632-641. *) equal contribution

11. Kim J, Hong G, Mazaleuskaya L, Hsu JC, Rosario-Berrios DN, Grosser T, Cho-Park PF, Cormode DP. Ultrasmall Antioxidant Cerium Oxide Nanoparticles for Regulation of Acute Inflammation. ACS Appl Mater Interfaces. 2021;13(51):60852-60864.

12. Myerson JW, Patel PN, Rubey KM, Zamora ME, Zaleski MH, Habibi N, Walsh LR, Lee YW, Luther DC, Ferguson LT, Marcos-Contreras OA, Glassman PM, Mazaleuskaya LL, Johnston I, Hood ED, Shuvaeva T, Wu J, Zhang HY, Gregory JV, Kiseleva RY, Nong J, Grosser T, Greineder CF, Mitragotri S, Worthen GS, Rotello VM, Lahann J, Muzykantov VR, Brenner JS. Supramolecular arrangement of protein in nanoparticle structures predicts nanoparticle tropism for neutrophils in acute lung inflammation. Nat Nanotechnol. 2022;17(1):86-97.

13. Price TS, Lucitt MB, Wu W, Austin DJ, Pizarro A, Yocum AK, Blair IA, FitzGerald GA, Grosser T. EBP, a program for protein identification using multiple tandem mass spectrometry datasets. Mol Cell Proteomics. 2007;6:527-36.

14. Lucitt MB, Price TS, Pizarro A, Wu W, Yocum AK, Seiler C, Pack MA, Blair IA, Fitzgerald GA, Grosser T. Analysis of the zebrafish proteome during embryonic development. Mol Cell Proteomics. 2008;7:981-94.

15. Fong KP, Barry C, Tran AN, Traxler EA, Wannemacher KM, Tang HY, Speicher KD, Blair IA, Speicher DW, Grosser T, Brass LF. Deciphering the human platelet sheddome. Blood. 2011;117(1):e15-26.

16. Greene CS, Krishnan A, Wong AK, Ricciotti E, Zelaya RA, Himmelstein DS, Zhang R, Hartmann BM, Zaslavsky E, Sealfon SC, Chasman DI, FitzGerald GA, Dolinski K, Grosser T, Troyanskaya OG. Understanding multicellular function and disease with human tissue-specific networks. Nat Genet. 2015;47(6):569-76.

17. Brooks TG, Mrčela A, Lahens NF, Paschos GK, Grosser T, Skarke C, FitzGerald GA, Grant GR. Nitecap: An Exploratory Circadian Analysis Web Application. J Biol Rhythms. 2022;37(1):43-52.

18. Lordan R, FitzGerald GA, Grosser T. Reopening schools during COVID-19. Science. 2020 Sep 4;369(6508):1146.

19. Lordan R, Prior S, Hennessy E, Naik A, Ghosh S, Paschos GK, Skarke C, Barekat K, Hollingsworth T, Juska S, Mazaleuskaya LL, Teegarden S, Glascock AL, Anderson S, Meng H, Tang SY, Weljie A, Bottalico L, Ricciotti E, Cherfane P, Mrcela A, Grant G, Poole K, Mayer N, Waring M, Adang L, Becker J, Fries S, FitzGerald GA, Grosser T. Considerations for the Safe Operation of Schools During the Coronavirus Pandemic. Front Public Health. 2021;9:751451.