Directed keratinocyte migration into a wound site is essential for skin repair. Decreased migration results in a chronic wound, of which there are 2,600,000 yearly. Isoproterenol (ISO), a beta-agonist, has a unique effect on keratinocytes, decreasing ERK phosphorylation and inhibiting their migration. This is contrary to reports that show beta2adrenergic receptor (beta2-AR) agonist-mediated activation of ERK in other cell types. The observed beta2-AR inhibition of keratinocyte migration may have wide clinical implications since beta-AR agonists and antagonists are widely used drugs. Asthma affects an estimated 14.2 million Americans, yearly, most of whom are treated with beta2-AR agonists. Nearly 50 million Americans are hypertensive and are also treated commonly by beta-AR antagonists, also known as beta-blockers. Few studies have examined the effects of beta-agonists/antagonists on cutaneous wound healing and the preliminary data suggest that these may profoundly alter the wound healing process. The long-term goal of this work is to understand the mechanisms through which beta-AR agonists modulate migration in human keratinocytes. The hypothesis to be tested is that beta-AR agonists inhibit keratinocyte migration by activating signaling pathways that mediate migration inhibition or by directly interacting with transporters required for cell motility. The initial signaling pathways activated upon ISO binding will be defined and mechanisms of inhibition explored. Interaction between the beta2-AR and specific transporters, known to play a role in migration, will be examined. These investigations will describe the signaling cascades involved in beta-AR agonist-mediated inhibition of keratinocyte migration and wound healing and will hopefully forge the way for more focus on signaling in the field of keratinocyte migration. This might lead to a better understanding of general migration signaling pathways also relevant for embryogenesis, immune defense and cancer progression and provide potentially clinically significant information for the 60-70 million Americans who use beta-AR drugs. Receiving this award will provide me with the financial support and guidance necessary for development into an independent research in the field of Dermatology and will ultimately aid me in obtaining an Adjunct Professor position at UCDavis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01AR048827-02
Application #
6749522
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Program Officer
Moshell, Alan N
Project Start
2003-06-01
Project End
2008-05-31
Budget Start
2004-06-01
Budget End
2005-05-31
Support Year
2
Fiscal Year
2004
Total Cost
$106,204
Indirect Cost
Name
University of California Davis
Department
Dermatology
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
O'Leary, Andrew P; Fox, James M; Pullar, Christine E (2015) Beta-Adrenoceptor Activation Reduces Both Dermal Microvascular Endothelial Cell Migration via a cAMP-Dependent Mechanism and Wound Angiogenesis. J Cell Physiol 230:356-65
Pullar, Christine E; Le Provost, Gabrielle S; O'Leary, Andrew P et al. (2012) ?2AR antagonists and ?2AR gene deletion both promote skin wound repair processes. J Invest Dermatol 132:2076-84
Sivamani, Raja K; Pullar, Christine E; Manabat-Hidalgo, Catherine G et al. (2009) Stress-mediated increases in systemic and local epinephrine impair skin wound healing: potential new indication for beta blockers. PLoS Med 6:e12
Ghoghawala, Shahed Y; Mannis, Mark J; Pullar, Christine E et al. (2008) Beta2-adrenergic receptor signaling mediates corneal epithelial wound repair. Invest Ophthalmol Vis Sci 49:1857-63
Pullar, Christine E; Zhao, Min; Song, Bing et al. (2007) Beta-adrenergic receptor agonists delay while antagonists accelerate epithelial wound healing: evidence of an endogenous adrenergic network within the corneal epithelium. J Cell Physiol 211:261-72
Pullar, Christine E; Baier, Brian S; Kariya, Yoshinobu et al. (2006) beta4 integrin and epidermal growth factor coordinately regulate electric field-mediated directional migration via Rac1. Mol Biol Cell 17:4925-35
Pullar, Christine E; Rizzo, Amilcar; Isseroff, R Rivkah (2006) beta-Adrenergic receptor antagonists accelerate skin wound healing: evidence for a catecholamine synthesis network in the epidermis. J Biol Chem 281:21225-35
Pullar, Christine E; Grahn, Jennifer C; Liu, Wei et al. (2006) Beta2-adrenergic receptor activation delays wound healing. FASEB J 20:76-86
Pullar, Christine E; Isseroff, R Rivkah (2006) The beta 2-adrenergic receptor activates pro-migratory and pro-proliferative pathways in dermal fibroblasts via divergent mechanisms. J Cell Sci 119:592-602
Pullar, Christine E; Isseroff, R Rivkah (2005) Cyclic AMP mediates keratinocyte directional migration in an electric field. J Cell Sci 118:2023-34

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