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REGULATION OF IL4 SIGNAL TRANSDUCITON BY POLY (ADP-RIBOSE) POLYMERASE-1.

Award Number: F30HL097580
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 08/01/2009
PERIOD OF PERFORMANCE END DATE: 05/17/2012

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REGULATION OF IL4 SIGNAL TRANSDUCITON BY POLY (ADP-RIBOSE) POLYMERASE-1. - DESCRIPTION (provided by applicant): The rising incidence of asthma in the United States is an increasingly onerous public health concern. The disease is disproportionately problematic in urban areas. As a disease that has been linked to environmental triggers such as pollen and air pollutants, it is crucial that we study its pathogenesis. While there are treatments available for asthma today, they do not deal with refractory cases and the lack of treatments often prove fatal to the patients suffering from these refractory cases. The enzyme poly(ADP- ribose)polymerase-1 (PARP-1) has been established as a mediator of inflammation and a player in asthmic eosinophilia. We study PARP-1 inhibition using PARP-1 knockout mice or a novel PARP-1 inhibitor, TiQ. Increased PAR levels in the disease state shows that PARP-1 is activated in both the mouse model of asthma as well as in human asthma. Furthermore, PARP-1 inhibition curtails the inflammatory response in the mouse model of asthma as eosinophilia is dramatically reduced. Preliminary data show PARP-1 is involved in the signal transduction pathway of the IL-4 cytokine receptor. Intranasal administration of IL-4 fails to restore eosinophilia to PARP-1 knockout mice, but administration of IL-5 does restore airway eosinophilia. Thus, PARP-1 inhibition results in the interruption of the signal transduction pathway between IL-4 and IL-5. My first specific aim is to examine the effects of PARP-1 inhibition on the activation and expression of the various signal transduction components of IL-4 signal transduction pathway including JAK1, JAK3, STAT6, and GATA3. Western blotting will be used to examine levels of protein expression as well as phosphorylation. This will show us whether there is an interruption in the IL-4 signal propagation. We will also look at mRNA expression of the various genes of interest. We hypothesize that PARP-1 has a specific effect on STAT6 expression. My second specific aim is to examine the effects of PARP-1 inhibition on the translocation of STAT6 into the nucleus. Translocation is a critical step in the transduction of the IL-4 signal and PARP-1 may have a role in the process. We will examine STAT6 translocation using immunofluorescence techniques. The findings from each of the specific aims will be confirmed using an adenoviral vector to restore PARP-1 to the animals or cell suspension and looking for phenotype reversal. Environmental conditions have been shown to correlate chronic disease incidence as well as triggering actual asthmatic episodes. Given the data demonstrating that PARP-1 inhibition abates of pulmonary inflammation in the mouse model of asthma, it is important to study the role of PARP-1 in inflammation in order to develop strategies in dealing with the disease.


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: 2013 ( Subtotal = -$4,413 )
2013	2011	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER	433 BOLIVAR STREET	NEW ORLEANS	LA	70112	ORLEANS	USA	Cardiovascular Diseases Research	000	3	12/24/2012	NON-COMPETING CONTINUATION	-$4,413
														Subtotal = -$4,413

Issue Date FY: 2011 ( Subtotal = $33,593 )
2011	2011	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER	433 BOLIVAR STREET	NEW ORLEANS	LA	70112	ORLEANS	USA	Cardiovascular Diseases Research	000	3	7/21/2011	NON-COMPETING CONTINUATION	$33,593
														Subtotal = $33,593

Issue Date FY: 2010 ( Subtotal = $33,173 )
2010	2010	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER	433 BOLIVAR STREET	NEW ORLEANS	LA	70112	ORLEANS	USA	Cardiovascular Diseases Research	000	2	8/10/2010	NON-COMPETING CONTINUATION	$33,173
														Subtotal = $33,173

Issue Date FY: 2009 ( Subtotal = $28,599 )
2009	2009	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER	433 BOLIVAR STREET	NEW ORLEANS	LA	70112	ORLEANS	USA	Cardiovascular Diseases Research	000	1	7/28/2009	NEW	$28,599
2009	2009	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER	433 BOLIVAR STREET	NEW ORLEANS	LA	70112	ORLEANS	USA	Cardiovascular Diseases Research	001	1	9/9/2009	NEW	$0
														Subtotal = $28,599

Grand Total All Awards = $90,952

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REGULATION OF IL4 SIGNAL TRANSDUCITON BY POLY (ADP-RIBOSE) POLYMERASE-1.

Award Number: F30HL097580

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 08/01/2009

PERIOD OF PERFORMANCE END DATE: 05/17/2012

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