Tuesday, December 3, 2024 12/3/2024

Human CYP2A and respiratory tract xenobiotic toxicity

Award Number: R01CA092596
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer-related death in the U.S., and tobacco smoke (TS) exposure is the most important contributing factor. However, while much has been learned about the tumorigenic effects and the underlying mechanisms of many individual tobacco carcinogens, relatively little is known about the mechanisms of carcinogenesis induced by TS, the actual complex environmental mixture that many people are exposed to on a daily basis. The in vivo contribution of specific carcinogens and their bioactivation to TS-induced lung tumorigenesis, or to TS-induced pathologic changes that precede carcinogenesis, such as lung inflammation, is largely unknown; but such knowledge is critical for designing effective chemoprevention for TS-induced lung toxicity and for assessing the safety of new tobacco products. The long-term objective of this grant has been to determine the role of respiratory tract cytochrome P450 (P450 or CYP) enzymes in the metabolic activation and toxicity of environmental chemicals, with a focus on CYP2A13, a human enzyme selectively expressed in the respiratory tract. Our central hypothesis is that CYP2A13 plays a vital role in tobacco-related lung carcinogenesis. The ability of CYP2A13 to mediate lung tumorigenesis induced by a major tobacco carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), is now well-documented, e.g., by our studies of CYP2A13-humanized mice. CYP2A13 also bioactivates many other TS toxicants/carcinogens. Epidemiologic studies of the CYP2A13*2 allele further support an important role of CYP2A13 in lung cancer risk in human smokers. A logical next step is to directly determine the role of CYP2A13 in TS-induced lung tumorigenesis. Thus, we will determine the in vivo role of human CYP2A13 and other P450 enzymes encoded by the mouse and human CYP2ABFS gene cluster in environmental tobacco smoke (ETS)-induced lung tumorigenesis (Aim 1) and lung inflammation (Aim 2); the latter is linked with both tumor initiation and tumor promotion. In Aim 1, we will test the hypothesis that deletion of mouse Cyp2abfs and addition of human CYP2A13 will lead to corresponding changes in the extent of lung tumorigenesis and the levels of O6-methylguanine (O6-mG) DNA adduct in the lung, in mice exposed chronically to ETS. In Aim 2, we will test the hypothesis that unique subsets of ETS constituents, which depend on CYP2A/B/F/S enzymes for bioactivation, enable ETS to cause lung inflammation in vivo. Our goal is to establish CYP2A13 as a valid genetic marker for lung cancer risk assessment and a logical molecular target for chemoprevention.


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: 2024 ( Subtotal = $0 )
2024	2020	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Cancer Cause and Prevention Research	000	16	2/28/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cancer Cause and Prevention Research	000	16	6/16/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $389,665 )
2020	2020	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cancer Cause and Prevention Research	000	16	7/17/2020	NON-COMPETING CONTINUATION	$389,665
														Subtotal = $389,665

Issue Date FY: 2019 ( Subtotal = $422,292 )
2019	2019	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cancer Cause and Prevention Research	001	15	7/30/2019	NON-COMPETING CONTINUATION	$378,238
2019	2017	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cancer Cause and Prevention Research	000	13	2/12/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$44,054
														Subtotal = $422,292

Issue Date FY: 2018 ( Subtotal = $390,319 )
2018	2018	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cancer Cause and Prevention Research	005	14	7/23/2018	NON-COMPETING CONTINUATION	$390,319
2018	2017	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cancer Cause and Prevention Research	004	13	4/2/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$84,685
2018	2017	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	257 FULLER RD	ALBANY	NY	12203	ALBANY	USA	Cancer Cause and Prevention Research	003	12	4/2/2018	NON-COMPETING CONTINUATION	-$105
2018	2017	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cancer Cause and Prevention Research	001	13	1/30/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$358,830
2018	2017	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	257 FULLER RD	ALBANY	NY	12203	ALBANY	USA	Cancer Cause and Prevention Research	000	12	1/30/2018	NON-COMPETING CONTINUATION	-$358,830
2018	2016	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	257 FULLER RD	ALBANY	NY	12203	ALBANY	USA	Cancer Cause and Prevention Research	002	11	4/2/2018	COMPETING CONTINUATION	-$84,580
														Subtotal = $390,319

Issue Date FY: 2017 ( Subtotal = $358,935 )
2017	2017	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	257 FULLER RD	ALBANY	NY	12203	ALBANY	USA	Cancer Cause and Prevention Research	003	12	7/12/2017	NON-COMPETING CONTINUATION	$358,935
2017	2016	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	257 FULLER RD	ALBANY	NY	12203	ALBANY	USA	Cancer Cause and Prevention Research	002	11	10/24/2016	COMPETING CONTINUATION	$842
2017	2014	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Family Smoking Prevention and Tobacco Control Act Regulatory Research	001	10	10/24/2016	SUPPLEMENT FOR EXPANSION	-$1
2017	2012	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Cancer Biology Research	000	10	10/24/2016	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$841
														Subtotal = $358,935

Issue Date FY: 2016 ( Subtotal = $381,584 )
2016	2016	RESEARCH FOUNDATION OF STATE UNIV OF NEW YORK (SUNY)	P.O. BOX 9	ALBANY	NY	12201	ALBANY	USA	Cancer Cause and Prevention Research	000	11	9/12/2016	COMPETING CONTINUATION	$381,584
														Subtotal = $381,584

Issue Date FY: 2014 ( Subtotal = $1 )
2014	2014	RESEARCH FOUNDATION OF STATE UNIV OF NEW YORK (SUNY)	P.O. BOX 9	ALBANY	NY	12201	ALBANY	USA	Family Smoking Prevention and Tobacco Control Act Regulatory Research	007	10	9/22/2014	SUPPLEMENT FOR EXPANSION	$1
2014	2014	RESEARCH FOUNDATION OF STATE UNIV OF NEW YORK (SUNY)	P.O. BOX 9	ALBANY	NY	12201	ALBANY	USA	Family Smoking Prevention and Tobacco Control Act Regulatory Research	003	10	9/17/2014	SUPPLEMENT FOR EXPANSION	$160,000
2014	2014	RESEARCH FOUNDATION OF STATE UNIV OF NEW YORK (SUNY)	P.O. BOX 9	ALBANY	NY	12201	ALBANY	USA	Family Smoking Prevention and Tobacco Control Act Regulatory Research	006	10	9/18/2014	SUPPLEMENT FOR EXPANSION	-$160,000
2014	2013	HEALTH RESEARCH, INC - ALBANY DIVISION	1 UNIVERSITY PLACE	RENSSELAER	NY	12144	RENSSELAER	USA	Family Smoking Prevention and Tobacco Control Act Regulatory Research	005	9	9/18/2014	SUPPLEMENT FOR EXPANSION	$160,000
2014	2013	HEALTH RESEARCH, INC - ALBANY DIVISION	1 UNIVERSITY PLACE	RENSSELAER	NY	12144	RENSSELAER	USA	Family Smoking Prevention and Tobacco Control Act Regulatory Research	004	9	9/17/2014	SUPPLEMENT FOR EXPANSION	-$160,000
2014	2012	RESEARCH FOUNDATION OF STATE UNIV OF NEW YORK (SUNY)	P.O. BOX 9	ALBANY	NY	12201	ALBANY	USA	Cancer Biology Research	002	10	9/16/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$80,000
2014	2012	HEALTH RESEARCH, INC - ALBANY DIVISION	1 UNIVERSITY PLACE	RENSSELAER	NY	12144	RENSSELAER	USA	Cancer Biology Research	001	9	9/16/2014	NON-COMPETING CONTINUATION	-$80,000
2014	2012	HEALTH RESEARCH, INC - ALBANY DIVISION	1 UNIVERSITY PLACE	RENSSELAER	NY	12144	RENSSELAER	USA	Cancer Biology Research	000	9	6/12/2014	NON-COMPETING CONTINUATION	$0
														Subtotal = $1

Issue Date FY: 2013 ( Subtotal = $371,520 )
2013	2013	HEALTH RESEARCH, INC - ALBANY DIVISION	1 UNIVERSITY PLACE	RENSSELAER	NY	12144	RENSSELAER	USA	Family Smoking Prevention and Tobacco Control Act Regulatory Research	000	9	8/2/2013	SUPPLEMENT FOR EXPANSION	$371,520
														Subtotal = $371,520

Issue Date FY: 2012 ( Subtotal = $691,719 )
2012	2012	HEALTH RESEARCH, INC - ALBANY DIVISION	1 UNIVERSITY PLACE	RENSSELAER	NY	12144	RENSSELAER	USA	Cancer Cause and Prevention Research	001	9	9/17/2012	SUPPLEMENT FOR EXPANSION	$370,171
2012	2012	HEALTH RESEARCH, INC - ALBANY DIVISION	1 UNIVERSITY PLACE	RENSSELAER	NY	12144	RENSSELAER	USA	Cancer Biology Research	000	9	7/4/2012	NON-COMPETING CONTINUATION	$321,548
2012	2012	HEALTH RESEARCH, INC - ALBANY DIVISION	1 UNIVERSITY PLACE	RENSSELAER	NY	12144	RENSSELAER	USA	Cancer Cause and Prevention Research	002	9	9/18/2012	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $691,719

Issue Date FY: 2011 ( Subtotal = $324,621 )
2011	2011	HEALTH RESEARCH, INC - ALBANY DIVISION	1 UNIVERSITY PLACE	RENSSELAER	NY	12144	RENSSELAER	USA	Cancer Biology Research	000	8	7/26/2011	EXTENSION WITH OR WITHOUT FUNDS	$324,621
														Subtotal = $324,621

Issue Date FY: 2010 ( Subtotal = $333,739 )
2010	2010	HEALTH RESEARCH, INC - ALBANY DIVISION	1 UNIVERSITY PLACE	RENSSELAER	NY	12144	RENSSELAER	USA	Trans-NIH Recovery Act Research Support	000	7	6/29/2010	NON-COMPETING CONTINUATION	$333,739
														Subtotal = $333,739

Issue Date FY: 2009 ( Subtotal = $330,142 )
2009	2009	HEALTH RESEARCH, INC - ALBANY DIVISION	1 UNIVERSITY PLACE	RENSSELAER	NY	12144	RENSSELAER	USA	Trans-NIH Recovery Act Research Support	003	6	8/12/2009	COMPETING CONTINUATION	$323,959
2009	2009	HEALTH RESEARCH, INC - ALBANY DIVISION	1 UNIVERSITY PLACE	RENSSELAER	NY	12144	RENSSELAER	USA	Trans-NIH Recovery Act Research Support	004	6	9/11/2009	COMPETING CONTINUATION	$6,183
2009	2007	HEALTH RESEARCH, INC - ALBANY DIVISION	1 UNIVERSITY PLACE	RENSSELAER	NY	12144	RENSSELAER	USA	Cancer Cause and Prevention Research	000	5	3/12/2009	NON-COMPETING CONTINUATION	$0
2009	2007	HEALTH RESEARCH, INC - ALBANY DIVISION	1 UNIVERSITY PLACE	RENSSELAER	NY	12144	RENSSELAER	USA	Cancer Cause and Prevention Research	002	5	9/9/2009	NON-COMPETING CONTINUATION	$0
2009	2007	HEALTH RESEARCH, INC - ALBANY DIVISION	1 UNIVERSITY PLACE	RENSSELAER	NY	12144	RENSSELAER	USA	Cancer Cause and Prevention Research	001	5	8/12/2009	NON-COMPETING CONTINUATION	$0
														Subtotal = $330,142

Issue Date FY: 2007 ( Subtotal = $480,409 )
2007	2007	HEALTH RESEARCH, INC - ALBANY DIVISION	1 UNIVERSITY PLACE	RENSSELAER	NY	12144	RENSSELAER	USA	Cancer Cause and Prevention Research	000	5	3/14/2007	NON-COMPETING CONTINUATION	$480,409
														Subtotal = $480,409

Grand Total All Awards = $6,088,752

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Human CYP2A and respiratory tract xenobiotic toxicity

Award Number: R01CA092596

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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