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Experimental Cellular Approaches to Genotype × Environment Interaction

Award Number: RM1GM149403
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: 09/07/2023
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Experimental Cellular Approaches to Genotype × Environment Interaction - PROJECT SUMMARY We propose to perform a novel study in the field of cellular epidemiology, that has been made possible by the recent revolution in induced pluripotent stem cell (iPSC) technology. It is well known that there are many cell- specific functions and behaviors that have been missed by the limitations of having to rely on easily obtainable cells, such as blood cells or lymphoblastoid cell lines, for epidemiological studies of disease causation, risk factors, and biomarker identification. Advances in iPSC technologies now allow us to consider non-invasive large-scale deep cellular phenotyping efforts on disease-appropriate cell types in human subjects. Robust derivation of iPSC lines and their differentiation into organ-specific cell types is possible from blood cells. An important benefit of iPSC-derived cells is that observed biological variation primarily represents genetic influences, since most of the epigenetic memory of the historical organismal environment is lost. Our proposed study involves an innovative experimental approach to human genotype×environment interaction (GEI). While GEI is thought to exist widely, it is relatively poorly studied in humans due to environmental heterogeneity and the difficulty of controlling environmental exposures. Our iPSC-based cellular approach allows us to rigorously test for GEI experimentally by examining cellular phenotypic variation before and after a controlled environmental challenge. Our study will be the first and largest study to model human GEI in two different iPSC-derived cell types. First, we will determine if the expected neurotoxic effect of snake venom in neural stem cells (NSCs) is genetically driven, and secondly, whether the suspected differential response of alveolar epithelial type 2 cells (AT2s) to environmental pollutant exposure has a genetic basis. This project will leverage a major existing human resource, the Mexican American Family Study (MAFS). We will use existing cryo-preserved iPSC lines from 400 MAFS participants for the generation of well-characterized NSCs and AT2. We propose a novel experimental and efficient pedigree-based approach for studying the genetic basis of cellular response to environmental stress (i.e, GEI), which has previously been difficult to assess. Our aims are: 1) assess genetic basis of NSC response to snake venom; 2) assess genetic basis of AT2 response to a benzo[a]pyrene pollution; 3) examine the genetic basis of environmental disruption of cellular transcriptional coherence/homeostasis; and 4) identify pleiotropic effects of cellular stress resilience on human organismal phenotypes relevant to health. This project will employ a novel experimental and efficient pedigree-based approach for studying human GEI, which has previously been difficult to assess. It also will help establish the feasibility of epidemiological scale utilization of iPSC technology to attack biomedical problems. Finally, we expect that the proposed project will rigorously establish the cellular basis of GEI influencing complex phenotypes of relevance to human health.


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 = $1,705,033 )
2025	2025	THE UNIVERSITY OF TEXAS RIO GRANDE VALLEY	1201 W UNIVERSITY DR	EDINBURG	TX	78539	HIDALGO	USA	Biomedical Research and Research Training	002	3	8/26/2025	SUPPLEMENT FOR EXPANSION	$61,342
2025	2025	THE UNIVERSITY OF TEXAS RIO GRANDE VALLEY	1201 W UNIVERSITY DR	EDINBURG	TX	78539	HIDALGO	USA	Biomedical Research and Research Training	001	3	8/11/2025	NON-COMPETING CONTINUATION	$1,597,684
2025	2025	THE UNIVERSITY OF TEXAS RIO GRANDE VALLEY	1201 W UNIVERSITY DR	EDINBURG	TX	78539	HIDALGO	USA	Biomedical Research and Research Training	000	2	11/20/2024	SUPPLEMENT FOR EXPANSION	$46,007
														Subtotal = $1,705,033

Issue Date FY: 2024 ( Subtotal = $1,611,736 )
2024	2024	THE UNIVERSITY OF TEXAS RIO GRANDE VALLEY	1201 W UNIVERSITY DR	EDINBURG	TX	78539	HIDALGO	USA	Biomedical Research and Research Training	000	2	8/27/2024	NON-COMPETING CONTINUATION	$1,611,736
														Subtotal = $1,611,736

Issue Date FY: 2023 ( Subtotal = $1,617,775 )
2023	2023	THE UNIVERSITY OF TEXAS RIO GRANDE VALLEY	1201 W UNIVERSITY DR	EDINBURG	TX	78539	HIDALGO	USA	Biomedical Research and Research Training	000	1	9/7/2023	NEW	$1,617,775
														Subtotal = $1,617,775

Grand Total All Awards = $4,934,544

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Experimental Cellular Approaches to Genotype × Environment Interaction

Award Number: RM1GM149403

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: 09/07/2023

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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