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Role of African-centric TP53 variant in higher H. pylori prevalence in African Americans

Award Number: R01DK124385
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Role of African-centric TP53 variant in higher H. pylori prevalence in African Americans - Project Summary African Americans have a 6-fold higher H. pylori (Hp) infection than the non-Hispanic white population; however, underlying gene(s) for this disparity remain elusive. We discovered that a human TP53 gene variant at amino acid 47 exists predominantly in people of African descent. Macrophages containing the S47 variant are defective in ferroptosis, M2 polarized and show more productive infections by Hp and other bacteria. Macrophage adaptive response is essential for eliminating Hp infection and is suppressed in chronic infections that lead to gastritis. Our collaborator, Dr. Keith Wilson, reported the role of Arg2 activation by Hp in suppressing the macrophage response. Unbiased WT and S47 macrophage proteomics revealed marked differences in Liver X Receptor activation, arginase II activity, inflammation, iron transport and antibacterial defense machinery which regulate immune response and directly affect outcomes of bacterial infections. Although p53 is known to regulate immune response, we are the first to discover the exact genetic variant causing the disparities. We will reverse the Hp infection disparities in African Americans with the S47 SNP by in-depth mechanistic and therapeutic study. Our human studies will give translational relevance to this project. We will test ~500 Hp seropositive African American samples for the prevalence of S47 and other SNPs. Then we will focus on improving macrophage response, Hp clearance and reduce chronic gastric dysplasia in S47 mice using Liver X Receptor (LXR) agonists. We will test if LXR activation improves these outcomes for multiple Hp strains with differing virulence. Moreover, we will generate a genome-wide map of macrophage binding of LXR to ‘fine tune’ its activity on macrophage activation and eliminate undesired effect of hepatic steatosis. Since Hp is found both extracellularly and within macrophages, specific depletion of immune cells will be used to distinguish the role of macrophages from other tissue environment in H. pylori pathogenesis. These studies will be validated by bone marrow swaps between WT and S47 mice. we will test macrophage regulation and tissue environment for more. We will prioritize and test pathways associated with LXR such as arginase pathway (Arg2, Slc7a2), iron transport (Tfrc, Slc40a1, Fth1) and innate immune proteins (TLR3 and TLR7) as novel therapeutic targets. Lastly, we will test macrophage regulatory factors (NOTCH1 and mTOR), energy metabolism (switching from ox-phos to glycolysis by Metformin) and polyamine pathway (DFMO-polyamine synthesis inhibitor) in fine tuning LXR agonist induced reversal of anti-inflammatory polarization in S47 mice, clearance of Hp infection and reduction of gastric dysplasia. This proposal will a) improve our understanding of the biological mechanism for the disparity in Hp infection in African Americans and b) provide several therapeutic avenues to improve clearance of Hp infection and gastritis. This project is a stepping stone for human studies in personalized medicine to address this health disparity. Hp infection has been deemed of critical importance in the African American minority, by the NIDDK.


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: 2025 ( Subtotal = $540,314 )
2025	2025	THE WISTAR INSTITUTE OF ANATOMY AND BIOLOGY	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	12/13/2024	NON-COMPETING CONTINUATION	$540,314
														Subtotal = $540,314

Issue Date FY: 2024 ( Subtotal = $576,336 )
2024	2024	THE WISTAR INSTITUTE OF ANATOMY AND BIOLOGY	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	5/14/2024	NON-COMPETING CONTINUATION	$36,022
2024	2024	THE WISTAR INSTITUTE OF ANATOMY AND BIOLOGY	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	12/15/2023	NON-COMPETING CONTINUATION	$540,314
														Subtotal = $576,336

Issue Date FY: 2023 ( Subtotal = $600,349 )
2023	2023	WISTAR INSTITUTE OF ANATOMY AND BIOLOGY, THE	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	1/9/2023	NON-COMPETING CONTINUATION	$600,349
														Subtotal = $600,349

Issue Date FY: 2022 ( Subtotal = $600,349 )
2022	2022	WISTAR INSTITUTE OF ANATOMY AND BIOLOGY, THE	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	12/15/2021	NON-COMPETING CONTINUATION	$540,314
2022	2022	WISTAR INSTITUTE OF ANATOMY AND BIOLOGY, THE	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	3/25/2022	NON-COMPETING CONTINUATION	$60,035
														Subtotal = $600,349

Issue Date FY: 2021 ( Subtotal = $636,016 )
2021	2021	WISTAR INSTITUTE OF ANATOMY AND BIOLOGY, THE	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	9/21/2021	NEW	$0
2021	2021	WISTAR INSTITUTE OF ANATOMY AND BIOLOGY, THE	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	1/19/2021	NEW	$636,016
														Subtotal = $636,016

Grand Total All Awards = $2,953,364

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Role of African-centric TP53 variant in higher H. pylori prevalence in African Americans

Award Number: R01DK124385

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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