We recently discovered the CATERPILLER family which share structural similarities with the NB-LRR (nucleotide-binding, leucine-rich repeat) super-family of disease resistance (R) proteins that constitutes the plant immune system. In the animal kingdom, this family is also known as NOD or NLR. The clinical importance of this family is underscored by the genetic linkage of family members to a number of immunologic disorders. Among the human gene family members, several of these appear to mediate negative regulatory function in controlling an overzealous inflammatory response. Most notable is the Monarch-1 protein which blocks the function of NF-kB inducing kinase (NIK). Inhibition of NIK reduces the expression of an array of chemokines with relevance in asthma. Gene profiling of induced sputum from mildly asthmatic individuals suggests that the Monarch-1 gene is reduced in these individuals relative to controls, supporting the inhibitory role of this gene during inflammation. Another group of family members regulates IL-1 production. Most notable among these is cryopyrin which mediates formation of the inflammasome complex upon stimulation with a number of inducers. The inflammasome complex is required for procaspase 1 processing to mature caspase 1. In turn, caspase-1 is required for the processing of pro-IL-1 and pro-IL-18 to their mature forms. IL-1 and IL-18 are respectively important in inflammation and TH2 skewing. Cryopyrin is also important in mediating macrophage necrosis which exacerbates inflammation. Thus there are compelling reasons to believe that Monarch-1 and cryopyrin have crucial roles in asthma, however there is no in vivo data to indicate that this is the case. Furthermore we have shown that both of these proteins are ATP-binding proteins, and they exhibit ATPase activity, thus providing ways to modulate their function, which might be important leads to drug discovery. The goals of this proposal are: (1) To study the relevance of Monarch-1 in three animal models of asthma (OVA-induced, endotoxin, and house dust mite and delineate the biochemical effects of Monarch-1 in vivo and ex vivo. (2) To study the relevance of cryopyrin and a cryopyrin-adaptor (ASC) in asthma. (3) To study and identify factors which modulate the nucleotide-binding properties and ATPase function of Monarch-1 and cryopyrin.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of North Carolina Chapel Hill
Chapel Hill
United States
Zip Code
Hua, Xiaoyang; Naselsky, Warren C; Jania, Corey M et al. (2016) Mast Cell Deficiency Limits the Development of Chronic Rhinosinusitis in Mice. Ann Otol Rhinol Laryngol 125:290-6
Kang, Min-Jong; Yoon, Chang Min; Kim, Bo Hye et al. (2015) Suppression of NLRX1 in chronic obstructive pulmonary disease. J Clin Invest 125:2458-62
Aleman, Maria M; Mills, Katherine; Almond, Martha et al. (2015) Reply: To PMID 25195169. J Allergy Clin Immunol 135:836-7
Wu, Weidong; Wages, Phillip A; Devlin, Robert B et al. (2015) SRC-mediated EGF receptor activation regulates ozone-induced interleukin 8 expression in human bronchial epithelial cells. Environ Health Perspect 123:231-6
Hernandez, Michelle L; Mills, Katherine; Almond, Martha et al. (2015) IL-1 receptor antagonist reduces endotoxin-induced airway inflammation in healthy volunteers. J Allergy Clin Immunol 135:379-85
Aleman, Maria M; Kesic, Matthew J; Mills, Katherine H et al. (2015) The IL-1 axis is associated with airway inflammation after O3 exposure in allergic asthmatic patients. J Allergy Clin Immunol 136:1099-101.e2
Bennett, William D; Alexis, Neil E; Almond, Martha et al. (2014) Effect of inhaled endotoxin on mucociliary clearance and airway inflammation in mild smokers and nonsmokers. J Aerosol Med Pulm Drug Deliv 27:459-65
Wu, Weidong; Muller, Robin; Berhane, Kiros et al. (2014) Inflammatory response of monocytes to ambient particles varies by highway proximity. Am J Respir Cell Mol Biol 51:802-9
Fry, Rebecca C; Rager, Julia E; Bauer, Rebecca et al. (2014) Air toxics and epigenetic effects: ozone altered microRNAs in the sputum of human subjects. Am J Physiol Lung Cell Mol Physiol 306:L1129-37
Brickey, Willie June (2013) Expression profiling to identify candidate genes associated with allergic phenotypes. Methods Mol Biol 1032:287-95

Showing the most recent 10 out of 56 publications