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REGULATION OF MUC19 BY TH2 CYTOKINE IN AIRWAY EPITHELIUM

Award Number: R01AI061695
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2007
PERIOD OF PERFORMANCE END DATE: 08/31/2012

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REGULATION OF MUC19 BY TH2 CYTOKINE IN AIRWAY EPITHELIUM - DESCRIPTION (provided by applicant): Airway mucus overproduction and epithelial mucous cell hyperplasia/metaplasia are clinical hallmarks associated with various airway diseases, such as COPD, cystic fibrosis and asthma. Despite the pathological significance of the excess mucus in these diseased airways, the cause and the mechanism of the aberrant mucus production is largely unknown. We have shown a "metaplastic" change of surface airway epithelial cells from the sole expression of the "surface" type of gel-forming mucin -MUC5AC to the co-expression with the submucosal gland-specific MUC5B and MUC19, a novel gel-forming we newly discovered, in airway diseases. Most recently, Muc19 locus has been shown to be genetically associated with salivary gland mucous cell development. A mouse having a single mutation (sld) in Muc19 locus shows mucous cell deficiency in their salivary gland. We have recently found that the mouse containing sld mutation also has much less submucosal gland mucous cells and less Muc19 expression. Thus, Muc19 locus appears to control glandular mucous cell development. Importantly, different from MUC5AC, which is elevated by IL-13 after long term treatment, this newly found gel-forming mucin gene-MUC19, can be stimulated by Th2 cytokines (IL-4 and IL-13) in a short-term (24h). Thus, we hypothesize that the induction of MUC19/Muc19 by Th2 cytokine may represent a key early event, seemingly to promote glandular phenotype, in the development of mucous cell metaplasia in asthmatic airway. To test the hypothesis, four aims are proposed: 1) To test the hypothesis that MUC19 production is significantly elevated in asthmatic airway. 2) To test the hypothesis that Muc19 expression is essential for mucous cell development. 2) To test the hypothesis that Th2 cytokine transcriptionally activates MUC19 gene expression in vitro. 3) To test the hypothesis that Th2 cytokine induced Muc19 expression and mucous cell metaplasia are regulated by the interaction of Stat1 and Stat6 in vivo. The success of this project will significantly advance our understanding of Th2 cytokine effect on development of epithelial mucus overproduction and mucous cell metaplasia, which will accelerate the development of specific epithelium-targeting therapeutic agents to treat asthma.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2011 ( Subtotal = $364,161 )
2011	2011	UNIVERSITY OF ARIZONA	POST OFFICE BOX 3308	TUCSON	AZ	85722		USA	Allergy and Infectious Diseases Research	000	6	8/15/2011	NON-COMPETING CONTINUATION	$364,161
														Subtotal = $364,161

Issue Date FY: 2010 ( Subtotal = $367,839 )
2010	2010	UNIVERSITY OF ARIZONA	POST OFFICE BOX 3308	TUCSON	AZ	85722		USA	Allergy and Infectious Diseases Research	000	5	8/6/2010	NON-COMPETING CONTINUATION	$367,839
														Subtotal = $367,839

Issue Date FY: 2009 ( Subtotal = $340,083 )
2009	2009	UNIVERSITY OF ARIZONA	POST OFFICE BOX 3308	TUCSON	AZ	85722		USA	Allergy and Infectious Diseases Research	002	4	7/21/2009	NON-COMPETING CONTINUATION	$370,532
2009	2008	UNIVERSITY OF ARIZONA	POST OFFICE BOX 3308	TUCSON	AZ	85722		USA	Allergy and Infectious Diseases Research	001	3	6/18/2009	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$270,459
2009	2008	THE HAMNER INSTITUTES	6 DAVIS DRIVE	RESEARCH TRIANGLE PARK	NC	27709	DURHAM	USA	Allergy and Infectious Diseases Research	000	2	6/18/2009	NON-COMPETING CONTINUATION	-$300,908
														Subtotal = $340,083

Issue Date FY: 2008 ( Subtotal = $412,020 )
2008	2008	THE HAMNER INSTITUTES	6 DAVIS DRIVE	RESEARCH TRIANGLE PARK	NC	27709	DURHAM	USA	Allergy and Infectious Diseases Research	000	2	8/5/2008	NON-COMPETING CONTINUATION	$412,020
														Subtotal = $412,020

Issue Date FY: 2007 ( Subtotal = $420,000 )
2007	2007	THE HAMNER INSTITUTES	6 DAVIS DRIVE	RESEARCH TRIANGLE PARK	NC	27709	DURHAM	USA	Allergy and Infectious Diseases Research	000	1	9/14/2007	NEW	$420,000
														Subtotal = $420,000

Grand Total All Awards = $1,904,103

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REGULATION OF MUC19 BY TH2 CYTOKINE IN AIRWAY EPITHELIUM

Award Number: R01AI061695

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/15/2007

PERIOD OF PERFORMANCE END DATE: 08/31/2012

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