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E-FABP mediates n-3 fatty acid-induced tumor prevention through epigenetic control of immune cell differentiation and function

Award Number: R01CA180986
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY/ABSTRACT Despite therapeutic advances, over 600,000 people in the US will die from cancer in 2019. Preventing cancer eliminates the risk of mortality and/or morbidity that may occur with the development of cancer. Thus, cancer prevention represents the most effective way for addressing cancer challenges. Healthy diet is considered be essential to reduce cancer risk by maintaining and improving immunity, but recent VITAL trials did not show beneficial effects of these supplements. The negative results reflect the mechanistic knowledge gap of how dietary factors modulate health. The objectives of this renewal application are to determine cellular and molecular mechanisms by which epithelial fatty acid binding protein (E-FABP) promotes n-3 fatty acid- mediated tumor prevention by enhancing immune cell differentiation and anti-tumor activity. Data collected in the last funding cycle have successfully established E-FABP as a new host-derived cancer prevention factor in non-obese subjects. During our studies, we observed that different types of high fat diets (HFD, 45% fat), including cocoa butter (rich in saturated fatty acids, FAs), safflower oil (rich in 18:2 linoleic acid), fish oil (rich in n-3 FAs), all induced similar degree of obesity in mouse models. However, tumor growth in these obese mice was dramatically different with the fastest growth in cocoa butter group and slowest in the fish oil group. In analyzing the immunophenotype of these obese mice, we found an atypical population of CD8+ ¿d T cells that was specifically upregulated in the fish oil group. More interestingly, fish oil diet-induced CD8+ ¿d T differentiation and anti-tumor effects were blunted in mice lacking E-FABP, suggesting a novel molecular mechanism mediated by E-FABP. Thus, we hypothesized that host expression of E-FABP plays a critical role in n-3 FA-induced immune cell differentiation and anti-tumor function. Three specific aims are proposed to address the central hypothesis in this renewal application. Specific Aim 1 will determine the mechanisms by which E-FABP promotes n-3 FA-induced immune cell differentiation. Experiments are designed to elucidate molecular mechanisms by which consumption of dietary n-3 FAs regulate CD8+ ¿d T cell differentiation via E- FABP-dependent epigenetic reprogramming. Specific Aim 2 will delineate how E-FABP mediates n-3 FA- induced anti-tumor activity. Results of Aim 2 are expected to reveal that E-FABP promotes host anti-tumor activity through targeting both immune cells and tumor-derived epithelial cells. Specific Aim 3 will evaluate whether targeting E-FABP with optimized n-3 FA diets results in effective tumor prevention. In summary, successful completion of this proposal will offer E-FABP as a new cancer prevention target and have significant mechanistic and clinical implications for healthy diet-mediated cancer prevention.


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 = $330,245 )
2024	2024	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cancer Cause and Prevention Research	000	10	11/30/2023	NON-COMPETING CONTINUATION	$312,864
2024	2024	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cancer Cause and Prevention Research	001	10	4/17/2024	NON-COMPETING CONTINUATION	$17,381
														Subtotal = $330,245

Issue Date FY: 2023 ( Subtotal = $340,673 )
2023	2023	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cancer Cause and Prevention Research	000	9	12/23/2022	NON-COMPETING CONTINUATION	$312,861
2023	2023	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cancer Cause and Prevention Research	003	9	3/17/2023	NON-COMPETING CONTINUATION	$27,812
2023	2021	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Cancer Cause and Prevention Research	001	6	3/9/2023	COMPETING CONTINUATION	-$54,528
2023	2021	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Cancer Cause and Prevention Research	002	6	3/9/2023	COMPETING CONTINUATION	$54,528
														Subtotal = $340,673

Issue Date FY: 2022 ( Subtotal = $340,673 )
2022	2022	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cancer Cause and Prevention Research	005	8	4/27/2022	NON-COMPETING CONTINUATION	$27,811
2022	2022	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cancer Cause and Prevention Research	002	8	12/29/2021	NON-COMPETING CONTINUATION	$312,862
2022	2021	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Cancer Cause and Prevention Research	003	6	1/4/2022	COMPETING CONTINUATION	$0
2022	2021	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cancer Cause and Prevention Research	004	7	1/4/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2022	2021	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cancer Cause and Prevention Research	001	7	12/1/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$56,897
2022	2021	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Cancer Cause and Prevention Research	000	6	12/1/2021	COMPETING CONTINUATION	$56,897
														Subtotal = $340,673

Issue Date FY: 2021 ( Subtotal = $347,747 )
2021	2021	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cancer Cause and Prevention Research	003	7	9/9/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$335,052
2021	2021	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Cancer Cause and Prevention Research	000	6	12/17/2020	COMPETING CONTINUATION	$351,000
2021	2021	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Cancer Cause and Prevention Research	002	6	9/8/2021	COMPETING CONTINUATION	-$338,305
2021	2018	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Cancer Cause and Prevention Research	001	5	2/8/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $347,747

Issue Date FY: 2018 ( Subtotal = $317,871 )
2018	2018	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Cancer Cause and Prevention Research	000	5	7/23/2018	NON-COMPETING CONTINUATION	$317,871
														Subtotal = $317,871

Issue Date FY: 2017 ( Subtotal = $318,006 )
2017	2017	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Cancer Cause and Prevention Research	000	4	7/20/2017	NON-COMPETING CONTINUATION	$318,006
														Subtotal = $318,006

Issue Date FY: 2016 ( Subtotal = $318,580 )
2016	2016	UNIVERSITY OF LOUISVILLE RESEARCH FOUNDATION	SERVICE COMPLEX	LOUISVILLE	KY	40292	JEFFERSON	USA	Cancer Cause and Prevention Research	000	3	6/30/2016	NON-COMPETING CONTINUATION	$318,580
														Subtotal = $318,580

Issue Date FY: 2015 ( Subtotal = $329,906 )
2015	2015	UNIVERSITY OF LOUISVILLE RESEARCH FOUNDATION	SERVICE COMPLEX	LOUISVILLE	KY	40292	JEFFERSON	USA	Cancer Cause and Prevention Research	001	2	6/24/2015	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$329,906
2015	2014	UNIVERSITY OF MINNESOTA, OFFICE OF STUDENT FINANCE AID	106 PLEASANT SE, 210 FRASER HL	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cancer Cause and Prevention Research	000	1	6/24/2015	NEW	$0
														Subtotal = $329,906

Issue Date FY: 2014 ( Subtotal = $322,969 )
2014	2014	UNIVERSITY OF MINNESOTA, OFFICE OF STUDENT FINANCE AID	106 PLEASANT SE, 210 FRASER HL	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cancer Cause and Prevention Research	000	1	7/25/2014	NEW	$322,969
														Subtotal = $322,969

Grand Total All Awards = $2,966,670

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E-FABP mediates n-3 fatty acid-induced tumor prevention through epigenetic control of immune cell differentiation and function

Award Number: R01CA180986

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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