Three distinct MAP kinase (MAPK) pathways, each mediated by the extracellular signal regulated protein kinases (ERK), the c-Jun N-terminal kinases (JNK) and the p38 MAPK, regulate the response of cells to a variety of extracellular stimuli. Under conditions of physical stress, tissue injury and infection, these MAPK signaling cascades are activated either in a direct, cell-autonomous manner or via intercellular cytokine signaling, and responsible for regulating cell survival and adaptation. In our long-term quest for understanding the function of MAPKs in the pathogenesis of inflammatory diseases, we have focused specifically on the p38 signaling pathway. Of the four isoforms of p38 MAPK in mammals, p38? is the most widely expressed protein and appears to mediate most, if not all, of the p38 MAPK actions that are sensitive to currently available p38 inhibitors. Targeted deletion of the p38? gene in mice results in early embryonic lethality, thus complicating the examination of p38 function in adult tissues. In this project, we aim to assess the cell type-specific requirement of p38? signaling in inflammatory responses and determine the mechanism by which p38? regulates inflammatory gene expression. To this end, we plan to pursue the following Specific Aims:1) Determine the cell type-specific functions of p38? in mouse models of inflammation;2) Identify the regulatory targets of p38? in myeloid, lymphoid, and epithelial tissues and determine their inflammatory function;and 3) Elucidate the mechanisms that link p38? signaling to target gene expression. Findings from the experiments proposed here will enable a better understanding of the p38 MAPK pathway and offer new insight into the treatment of inflammatory diseases. Public Health Relevance:
We aim to understand how injurious stimuli induce inflammatory responses through investigation of molecules that relay inflammatory signals in the cell. Our study will offer new insight into the treatment of inflammatory diseases.

Public Health Relevance

We aim to understand how injurious stimuli induce inflammatory responses through investigation of molecules that relay inflammatory signals in the cell. Our study will offer new insight into the treatment of inflammatory diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI074957-05
Application #
8440849
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Palker, Thomas J
Project Start
2009-04-20
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
5
Fiscal Year
2013
Total Cost
$357,584
Indirect Cost
$150,292
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Sano, Yasuyo; Park, Jin Mo (2014) Loss of epidermal p38? signaling prevents UVR-induced inflammation via acute and chronic mechanisms. J Invest Dermatol 134:2231-40
Mao, Xuming; Li, Hong; Sano, Yasuyo et al. (2014) MAPKAP kinase 2 (MK2)-dependent and -independent models of blister formation in pemphigus vulgaris. J Invest Dermatol 134:68-76
Caballero-Franco, Celia; Choo, Min-Kyung; Sano, Yasuyo et al. (2013) Tuning of protein kinase circuitry by p38* is vital for epithelial tissue homeostasis. J Biol Chem 288:23788-97
Katholnig, Karl; Kaltenecker, Christopher C; Hayakawa, Hiroko et al. (2013) p38ýý senses environmental stress to control innate immune responses via mechanistic target of rapamycin. J Immunol 190:1519-27
Carlson, Bradley A; Yoo, Min-Hyuk; Conrad, Marcus et al. (2011) Protein kinase-regulated expression and immune function of thioredoxin reductase 1 in mouse macrophages. Mol Immunol 49:311-6
Mao, Xuming; Sano, Yasuyo; Park, Jin Mo et al. (2011) p38 MAPK activation is downstream of the loss of intercellular adhesion in pemphigus vulgaris. J Biol Chem 286:1283-91