Project 1 (Broide) will investigate innate pathways that contribute to airway inflammation and airway remodeling in asthma. This project will focus on increasing our understanding of how a novel innate cell cytokine (Folistatin Like Protein-1 or FSL-1) as well as a novel innate cell population of pro-inflammatory natural helper cells (NHC) (small mononuclear cells that express high levels of Th2 cytokines, but no markers for T cells, NK cells, mononuclear cells, macrophages, mast cells) mediate important aspects of allergen induced airway inflammation and remodeling. Studies will examine how allergen exposure in atopic asthma activates these two novel interconnected innate pathways to promote airway inflammation and remodeling (i.e. activation of natural helper cells to express Th2 cytokines that subsequently activate M2 macrophages to express FSL-1 a pro-inflammatory and pro-remodeling gene with receptors on smooth muscle and blood vessels). The importance of these novel innate pathways to asthma will be examined by studying levels of their expression in asthma compared to healthy controls, as well as in asthmatics challenged with allergen or rhinovirus. In addition we will determine the stimuli that induce their expression, the distribution of receptors that mediate their activation, and the profile of mediators released following their activation that are important to inflammation and remodeling. Finally, although the major focus of this project will be on studying human asthmatics, mouse models will be used to answer mechanistic questions that are not ethical to perform in humans (such as administration of anti-FSL-1 Ab, and adoptive transfer or depletion of NHC). This research project will interact with both Project 2 (Croft), Project 3 (Zuraw) and Core B to gain insight into how allergen and viral triggers of asthma contribute to airway inflammation and remodeling in asthma.
Inhalation of airborne allergens such as cat and dust mite or respiratory viruses may result in damage and scarring of the bronchial tubes in susceptible asthmatics. This project will provide increased understanding of the cause of this scarring and suggest potential ways to identify asthmatics at risk for developing scarring of their lungs, or potential new treatments.
|Chang, Jinny E; Doherty, Taylor A; Baum, Rachel et al. (2014) Prostaglandin D2 regulates human type 2 innate lymphoid cell chemotaxis. J Allergy Clin Immunol 133:899-901.e3|
|Cho, Jae Youn; Doshi, Ashmi; Rosenthal, Peter et al. (2014) Smad3-deficient mice have reduced esophageal fibrosis and angiogenesis in a model of egg-induced eosinophilic esophagitis. J Pediatr Gastroenterol Nutr 59:10-6|
|Croft, Michael (2014) The TNF family in T cell differentiation and function--unanswered questions and future directions. Semin Immunol 26:183-90|
|Nonaka, Motohiro; Bao, Xingfeng; Matsumura, Fumiko et al. (2014) Synthetic di-sulfated iduronic acid attenuates asthmatic response by blocking T-cell recruitment to inflammatory sites. Proc Natl Acad Sci U S A 111:8173-8|
|Ge, Xiao Na; Ha, Sung Gil; Rao, Amrita et al. (2014) Endothelial and leukocyte heparan sulfates regulate the development of allergen-induced airway remodeling in a mouse model. Glycobiology 24:715-27|
|Miller, Marina; Rosenthal, Peter; Beppu, Andrew et al. (2014) ORMDL3 transgenic mice have increased airway remodeling and airway responsiveness characteristic of asthma. J Immunol 192:3475-87|
|Miyazaki, Masaki; Miyazaki, Kazuko; Chen, Shuwen et al. (2014) Id2 and Id3 maintain the regulatory T cell pool to suppress inflammatory disease. Nat Immunol 15:767-76|
|Cho, Jae Youn; Rosenthal, Peter; Miller, Marina et al. (2014) Targeting AMCase reduces esophageal eosinophilic inflammation and remodeling in a mouse model of egg induced eosinophilic esophagitis. Int Immunopharmacol 18:35-42|
|Suzukawa, Maho; Miller, Marina; Rosenthal, Peter et al. (2013) Sialyltransferase ST3Gal-III regulates Siglec-F ligand formation and eosinophilic lung inflammation in mice. J Immunol 190:5939-48|
|Croft, Michael; Benedict, Chris A; Ware, Carl F (2013) Clinical targeting of the TNF and TNFR superfamilies. Nat Rev Drug Discov 12:147-68|
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