Mitogen activated protein (MAP) kinases are serine/threonine kinases that mediate signal transduction and orchestrate cellular responses to environmental stress. In mammalian cells, three principle MAP kinase pathways have been identified, including c-Jun N-terminal kinase (JNK), extracellular regulating kinase (ERK), and p38 MAP kinase. p38 is thought to be especially relevant to rheumatoid arthritis (RA) because it is activated in RA synovium and regulates key mediators implicated in the disease. It is regulated by two main upstream MAP kinase kinases, namely MKK3 and MKK6. Despite pre-clinical evidence that p38 blockade should be beneficial in RA, only modest improvement has been noted in clinical trials when patients are treated with p38 inhibitors. This observation might be due to increased activation of ERK and JNK and suppression of anti-inflammatory cytokines like IL-10 by p38 inhibitors. Understanding the mechanisms that limit efficacy is crucial to developing effective new targeted therapies. We now hypothesize that targeting MKK3 or MKK6 might be more effective than traditional p38 inhibitors in diseases like RA. This proposal will explore the biology of MKK3, MKK6, and p38 and test our hypothesis by 1) determining if targeting MKK3 or MKK6 instead of p38 in murine arthritis models preserves IL-10 production and prevents increased activation of other MAP kinases; 2) determining the mechanisms of differential IL-10 regulation and ERK/JNK signaling by MKKs and p38 in cultured macrophages; and 3) determining if p38 blockade suppresses IL-10 and activates ERK/JNK in RA samples and whether this is prevented by targeting MKK3 or MKK6. In addition, a program to evaluate potential MKK3 and MKK6 inhibitors will be initiated to translate the results into a potential therapy. If successful, these studies will support development of novel MAP kinase kinase inhibitors for RA.

Public Health Relevance

Despite the introduction of biologics, rheumatoid arthritis remains an unmet medical need with a requirement for less expensive and more effective oral therapies. We have proposed targeting upstream kinases in the MAP kinase cascade to address this need. The planned experiments are highly relevant to the goals of the NIH because they focus on a novel therapy for rheumatoid arthritis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI070555-09
Application #
8824862
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Peyman, John A
Project Start
2006-05-15
Project End
2017-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
9
Fiscal Year
2015
Total Cost
$387,500
Indirect Cost
$137,500
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Nygaard, Gyrid; Di Paolo, Julie A; Hammaker, Deepa et al. (2018) Regulation and function of apoptosis signal-regulating kinase 1 in rheumatoid arthritis. Biochem Pharmacol 151:282-290
Firestein, Gary S; McInnes, Iain B (2017) Immunopathogenesis of Rheumatoid Arthritis. Immunity 46:183-196
Stanford, Stephanie M; Svensson, Mattias N D; Sacchetti, Cristiano et al. (2016) Receptor Protein Tyrosine Phosphatase ?-Mediated Enhancement of Rheumatoid Synovial Fibroblast Signaling and Promotion of Arthritis in Mice. Arthritis Rheumatol 68:359-69
Stanford, Stephanie M; Aleman Muench, German R; Bartok, Beatrix et al. (2016) TGF? responsive tyrosine phosphatase promotes rheumatoid synovial fibroblast invasiveness. Ann Rheum Dis 75:295-302
Ai, Rizi; Hammaker, Deepa; Boyle, David L et al. (2016) Joint-specific DNA methylation and transcriptome signatures in rheumatoid arthritis identify distinct pathogenic processes. Nat Commun 7:11849
Guma, M; Sanchez-Lopez, E; Lodi, A et al. (2015) Choline kinase inhibition in rheumatoid arthritis. Ann Rheum Dis 74:1399-407
Doody, Karen M; Stanford, Stephanie M; Sacchetti, Cristiano et al. (2015) Targeting phosphatase-dependent proteoglycan switch for rheumatoid arthritis therapy. Sci Transl Med 7:288ra76
Hammaker, Deepa; Boyle, David L; Topolewski, Katharyn et al. (2014) Differential regulation of anti-inflammatory genes by p38 MAP kinase and MAP kinase kinase 6. J Inflamm (Lond) 11:14
Leinders, Mathias; Koehrn, Fred J; Bartok, Beatrix et al. (2014) Differential distribution of PI3K isoforms in spinal cord and dorsal root ganglia: potential roles in acute inflammatory pain. Pain 155:1150-60
Boyle, David L; Hammaker, Deepa; Edgar, Meghan et al. (2014) Differential roles of MAPK kinases MKK3 and MKK6 in osteoclastogenesis and bone loss. PLoS One 9:e84818

Showing the most recent 10 out of 30 publications