Asthma is a chronic inflammatory disease of the lung and a significant health burden. Although appropriate usage of asthma medications successfully reduces impairment they do not slow progression and potentially increase risk of exacerbation. Asthma is also a heterogenous disease with various pathologic features and treatment-resistant subtypes. The following project aims to offer insight into sensory neuroplasticity, or how sensory neurons change in asthma, which is an established therapeutic target and useful tool to characterize asthma subtypes. Airway sensory neurons in asthma malfunction and cause airway hyperreactivity. The upstream changes to neuron structure and inciting factor behind sensory dysfunction are unknown due to obstacles in characterizing airway innervation. For the current project a novel method was developed permitting the visualization of whole airway innervation and computerized quantification of nerve branching and nerve density. We have shown that increased eosinophils in the airway results in a doubling of nerve branchpoints and length. The long term goal of this research is to use this technique in tandem with transgenic, in vitro, and molecular approaches to characterize and understand asthma-related sensory neuroplasticity. Guided by data from similar diseases and preliminary data, the current project will test if sensory neuron branching and density increases via eosinophils in two asthma models and if branched outgrowth correlates with increased sensory nerve-induced reflex bronchoconstriction. Preliminary data has already demonstrated some of these changes. This project will subsequently investigate the role of eosinophil-derived neurotrophins in producing asthma-related sensory neuroplasticity. The current project will use several mouse models of asthma including 1.) an valbumin sensitization and challenge model, 2.) transgenic mice lacking eosinophils, and 3.) transgenic mice exhibiting overabundant lung eosinophils. For the first aim, airway nerve branching and length will be quantified with computational nerve modeling and compared to a functional readout, that of reflex bronchoconstriction.
The second aim i s to investigate the role of eosinophil neurotrophin (NGF, BDNF, NT-3, NT-4) release on sensory neuroplasticity using a co-culture system. Eosinophil and sensory neuron co-cultures will be used with exogenous administration of neurotrophins, and neurotrophin blocking antibodies followed by quantification of neuron branched outgrowth.
The current proposal will utilize a novel technique to investigate outgrowth of airway sensory neurons as a cause of asthma, a common inflammatory lung disease. This work will aid in understanding asthma pathogenesis and identifying new therapeutic targets.
|Lee, James J; Protheroe, Cheryl A; Luo, Huijun et al. (2015) Eosinophil-dependent skin innervation and itching following contact toxicant exposure in mice. J Allergy Clin Immunol 135:477-87|
|Scott, Gregory D; Blum, Emily D; Fryer, Allison D et al. (2014) Tissue optical clearing, three-dimensional imaging, and computer morphometry in whole mouse lungs and human airways. Am J Respir Cell Mol Biol 51:43-55|
|Scott, Gregory D; Fryer, Allison D; Jacoby, David B (2013) Quantifying nerve architecture in murine and human airways using three-dimensional computational mapping. Am J Respir Cell Mol Biol 48:10-6|
|Drake, Matthew G; Scott, Gregory D; Proskocil, Becky J et al. (2013) Toll-like receptor 7 rapidly relaxes human airways. Am J Respir Crit Care Med 188:664-72|
|Scott, Gregory D; Fryer, Allison D (2012) Role of parasympathetic nerves and muscarinic receptors in allergy and asthma. Chem Immunol Allergy 98:48-69|
|Nie, Zhenying; Scott, Gregory D; Weis, Patrick D et al. (2011) Role of TNF-Î± in virus-induced airway hyperresponsiveness and neuronal Mâ‚‚ muscarinic receptor dysfunction. Br J Pharmacol 164:444-52|
|Braun, Theodore P; Zhu, Xinxia; Szumowski, Marek et al. (2011) Central nervous system inflammation induces muscle atrophy via activation of the hypothalamic-pituitary-adrenal axis. J Exp Med 208:2449-63|