A recently recognized role of nicotinic acetylcholine receptors (nAChR) is to regulate inflammatory cytokine expression. As we age, changes in nAChR expression are observed and these correlate with dysregulation of inflammatory status. This raises the relatively unexplored possibility that these age-related changes are mechanistically related. The skin exhibits age-related changes in nAChR expression and proinflammatory cytokine expression, and it is an experimentally accessible model for defining how nAChR expression impacts on both primary and secondary inflammatory responses. Recent key findings in the mouse skin include: 1) the nAChRa7 subtype modulates expression of suppressor of cytokine signaling 3 (SOCS3);2) the nAChR:inflammatory interaction involves p38MAPkinse responsive pathways;and 3) SOCS3 expression is dysregulated in both a7KO adult mice and aged mice whose a7 expression is dramatically decreased. Therefore, the goal of the research proposed is to elucidate mechanisms of interaction between the nAChR and the inflammatory cytokines in regulating peripheral responses as we age. Overall Project Hypothesis: Age-related shifts in nAChR expression by peripheral organs modulate local dysregulation of inflammatory responses through SOCS3 and p38MAPK-dependent pathways.
SPECIFIC AIM 1. Goal: To measure age-related changes in the inflammatory status and response by the skin and correlate these to age-related changes in nAChR expression. Hypothesis: Tissue-specific changes in nAChR expression will correspond to age-related alterations in responses to an inflammatory challenge.
SPECIFIC AIM 2. Goal: To define the intracellular signaling mechanism(s) that control interactions between nAChRs and inflammatory cytokines, and determine if alterations within these pathways correspond to age related dysfunction in nAChR:inflammatory balance. Hypothesis: nAChRa7 impacts upon inflammatory status through modulating intracellular signaling cascades affecting SOCS3 expression.
SPECIFIC AIM 3. Goal: One hypothesis of aging is that chronic inflammation speeds the progression of aging. Because a7KO mice demonstrate an exaggerated inflammatory response;chronic inflammatory stimulation should result in more rapid aging in terms of inflammatory cytokine production by the skin. Hypothesis: Adult mice lacking the expression of a7 will respond to chronic inflammatory challenge by exhibiting inflammatory characteristics consistent with more advanced aged phenotypes.

Public Health Relevance

Neuronal nicotinic receptors (nAChR) are normally studied for their role in the brain where they regulate processes leading to addiction. In addition to neurons, cells throughout the body express nAChRs where they to help regulate normal inflammatory responses to invading organisms. As we age, nAChR expression in peripheral tissues and the brain decreases. In turn, the ability of our body to control normal inflammatory responses also decreases. This proposal will investigate how nAChR expression can contribute to regulating inflammation through different pathways, especially as we age. Further, we will determine if changes in nAChR expression shape the progression of normal aging of the skin through altering the important balance between normal and excessive inflammation.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG029838-05
Application #
8306201
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Fuldner, Rebecca A
Project Start
2008-09-15
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2012
Total Cost
$234,870
Indirect Cost
$78,810
Name
University of Utah
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Gahring, Lorise C; Myers, Elizabeth; Palumbos, Sierra et al. (2014) Nicotinic receptor Alpha7 expression during mouse adrenal gland development. PLoS One 9:e103861
Gahring, Lorise C; Enioutina, Elena Y; Myers, Elizabeth J et al. (2013) Nicotinic receptor alpha7 expression identifies a novel hematopoietic progenitor lineage. PLoS One 8:e57481
Rogers, Scott W; Tvrdik, Petr; Capecchi, Mario R et al. (2012) Prenatal ablation of nicotinic receptor alpha7 cell lineages produces lumbosacral spina bifida the severity of which is modified by choline and nicotine exposure. Am J Med Genet A 158A:1135-44
Gahring, Lorise C; Vasquez-Opazo, Gustavo A; Rogers, Scott W (2010) Choline promotes nicotinic receptor alpha4 + beta2 up-regulation. J Biol Chem 285:19793-801
Gahring, Lorise C; Rogers, Scott W (2010) Nicotinic receptor subunit alpha5 modifies assembly, up-regulation, and response to pro-inflammatory cytokines. J Biol Chem 285:26049-57
Gahring, Lorise C; Osborne, Amber V; Reed, Michelle et al. (2010) Neuronal nicotinic alpha7 receptors modulate early neutrophil infiltration to sites of skin inflammation. J Neuroinflammation 7:38