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Expression genetics of pharmacogenes

Award Number: R35GM140845
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2021
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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Expression genetics of pharmacogenes - PROJECT SUMMARY The overarching goal of my research program is to gain a comprehensive understanding of the variability in drug metabolism to make drug therapies more effective and less toxic. The cytochrome P450 drug- metabolizing enzymes (dmCYPs) are the main enzymes that metabolize nearly 70% of the drugs currently used, which are highly variable from person to person, necessitating personalized drug therapy. Genetic factors significantly affect the drug metabolism, and the variants of some dmCYPs are used as clinical biomarkers to predict the metabolizer status. However, the underlying principles of their variable expression/activity are far from clear. Variants that result in altered amino acid sequences have been studied extensively, but they fail to account for all the differences observed. On the other hand, technical challenges have thus far limited the studies on factors that affect mRNA and protein expression of dmCYPs. Most dmCYPs are multi-gene clusters with complex genomic architecture and diverse genetic variations. With the support of NIGMS funding, we have adopted innovative methodologies and dissected the complex genomic architecture of multiple gene clusters (e. g., CYP3A) and identified hidden cis-acting regulatory variants that affect gene expression (e. g., 3A4, 3A5 and 3A43). Our results demonstrate that a single variant can have opposing effects on two genes in the same locus (e. g, 3A4, and 3A43), while more than one variant can regulate a single gene in the same or opposite direction (e. g., CYP7A1 and CYP2D6) indicating complex domain-domain interactions within the gene cluster and epistasis between variants. Such complexity usually escapes genome wide association study based discovery and warrants a dedicated approach proposed here. With the success of dissecting the CYP3A cluster, we now plan to expand and analyze the other dmCYP gene clusters over the next five years. Furthermore, we have recently identified ligand-free estrogen receptor alpha (ESR1) as a master regulator of CYP3A4 and many other dmCYP genes. Genetic, epigenetic, and non-genetic factors that affect ESR1-centered regulatory network will likely affect dmCYP gene expression and enzyme activity via trans-acting mechanisms. We plan to use ESR1-knockout hepatocytes differentiated from iPSC to characterize ESR1-centered regulatory network and to identify factors regulating ESR1 and dmCYPs expression. The identified functional cis and trans-acting genetic variants and epigenetic factors, including non-coding RNAs, will be tested in human liver samples for their impact on mRNA and protein expression of dmCYPs. The clinical significance of the identified variants will be tested in clinical cohort via collaboration. With my track record of pharmacogenetics biomarker discovery, insights gained from studying complex multi-gene clusters, availability of novel technologies, and support from collaborators with expertise in bioinformatics, proteomics and pharmacogenetics implementation, I am well positioned to undertake the proposed studies. The outcome will have immediate clinical translation leading to more accurate biomarkers for guiding personalized drug therapy.


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 = $326,888 )
2025	2025	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Biomedical Research and Research Training	001	5	1/2/2025	NON-COMPETING CONTINUATION	$326,888
2025	2024	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Biomedical Research and Research Training	000	4	11/15/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $326,888

Issue Date FY: 2024 ( Subtotal = $364,067 )
2024	2024	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Biomedical Research and Research Training	001	4	8/6/2024	NON-COMPETING CONTINUATION	$36,407
2024	2024	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Biomedical Research and Research Training	000	4	3/18/2024	NON-COMPETING CONTINUATION	$327,660
														Subtotal = $364,067

Issue Date FY: 2023 ( Subtotal = $365,629 )
2023	2023	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Biomedical Research and Research Training	000	3	2/1/2023	NON-COMPETING CONTINUATION	$329,066
2023	2023	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Biomedical Research and Research Training	001	3	4/6/2023	NON-COMPETING CONTINUATION	$36,563
														Subtotal = $365,629

Issue Date FY: 2022 ( Subtotal = $367,049 )
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Biomedical Research and Research Training	001	2	6/22/2022	NON-COMPETING CONTINUATION	$36,705
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Biomedical Research and Research Training	000	2	1/26/2022	NON-COMPETING CONTINUATION	$330,344
														Subtotal = $367,049

Issue Date FY: 2021 ( Subtotal = $368,340 )
2021	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Biomedical Research and Research Training	000	1	3/22/2021	NEW	$368,340
														Subtotal = $368,340

Grand Total All Awards = $1,791,973

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Expression genetics of pharmacogenes

Award Number: R35GM140845

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2021

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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