A Humanized Mouse Model of Severe Asthma

Mouse models containing single mutations help examine the role of specific pathways involved with the disease.

To study mechanisms of asthma and other allergic diseasesTo develop and test treatments of allergic diseases, including asthma, food allergy, and inflammatory bowel disease

UCLA researchers have developed 2 novel transgenic mouse models of the allergic response by using knock-in mutagenesis to create Q576R and Y709F mutants of the endogenous murine IL-4R . The Q576R mice, a human genetic polymorphism that is associated with severe and fatal and near-fatal asthma, developed severe allergic airway disease modeling human asthma. The Y709F mice, a key regulatory residue in the IL-4R alpha chain immunoreceptor tyrosine based inhibitory motif (ITIM), exhibited heightened allergic responses and allergic airway disease. Both mutations were found to promote IL-4 production by Th2 cells and IgE responses.

State Of Development

The mouse models are fully developed. The researchers plan to employ the model in studies of asthma and food allergies including drug screening

Background

Asthma, a chronic inflammatory disease of the lung, affects an increasingly larger population every year and presents a major public health problem in terms of morbidity and cost. The cause and mechanisms of asthma and allergic diseases are not yet understood. As the spontaneous development of asthma in a non-human animal is next to impossible, the ability to engineer mouse models of the disease remains critical to the understanding and treatment of the disease.

Related Materials

Reference for the Q576R mouse Tachdjian R, Mathias C, Al Khatib S, Bryce PJ, Kim HS, Blaeser F, O'Connor BD, Rzymkiewicz D, Chen A, Caplan B, Holtzman MJ, Hershey GK, Garn H, Harb H, Renz H, Oettgen HC, Chatila TA. Pathogenicity of a Disease-Associated Human IL-4 Receptor Allele in Experimental Asthma, Journal of Experimental Medicine. vol. 206 (10): 2191 (2009).
Tachdjian R, Al Khatib S, Schwinglshackl A, Kim HS, Chen A, Blasioli J, Mathias C, Kim HY, Umetsu DT, Oettgen HC, Chatila TA. In vivo regulation of the allergic response by the IL-4 receptor alpha chain immunoreceptor tyrosine-based inhibitory motif. J Allergy Clin Immunol. vol 125(5):1128-1136.e8. Epub 2010 Apr 14. (2010)
Reference for IL-4 receptor signaling pathways in asthma: Chatila TA. "Interleukin 4 Receptor Signaling Pathways in Asthma Pathogenesis," Trends in Molecular Medicine, Vol. 10. p. 493-9 (2004).

Tech ID/UC Case

21512/2010-090-0

Related Cases

2010-090-0

USA