Saturday, November 23, 2024 11/23/2024

Characterizing and Understanding Variation in Gene Regulatory Mechanisms Within and Between Species

Award Number: R35GM131726
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Abstract: Understanding the genetic basis of gene regulation is key to understanding the evolutionary processes that have shaped specific traits in humans and non-human apes. In turn, identifying and characterizing the genetic variants that lead to inter-individual responses to different exposures is critical to gain insight into gene by environment interactions and associated phenotypic consequences. By elucidating the genetic variation that underlies regulatory differences between species, and the genetic variation that is associated with individual differences in response to environmental cues, we can gain a better understanding of the evolutionary processes that led to human-specific traits, as well as the genetic basis of complex traits and diseases. The challenge is that to carry out this work in humans and other apes, one must rely on in vitro systems. During the first term of the MIRA award, my lab focused on understanding the molecular mechanisms that underlie the evolution of gene expression, such as natural selection, the influence of epigenetic marks, and the effects of gene duplication. We developed and broadly shared a comparative panel of iPSCs from humans and chimpanzees, and we established a new approach for iPSC differentiation (we call it ‘guided differentiation’), which makes it feasible for us to study gene regulation across a broad range of cell types and contexts. We used these systems to study the impact of variation in gene regulatory networks on complex diseases and the role of gene regulation in the generation of phenotypic diversity. We explored the roles of gene expression in human diseases, such as cancer and neurological disorders, and developed methods for analyzing comparative single-cell gene expression data. In the next term of this award, we propose to continue to study similar broad areas. We will sharpen our focus on gene by environment interactions and develop a better understanding of the genetic variation that leads to regulatory variation in response to different exposures. We will employ a dynamic eQTL mapping approach to offer additional insight into the genetic basis for disease. We will also explore the role of epigenetic mechanisms, such as DNA methylation, histone modifications, and non-coding RNAs, in mediating gene by environment interactions. We will use the comparative iPSC panel to explore the relative impact and evolutionary consequences of changes in cis and trans regulatory mechanisms in dozens of different tissues and cell types and continue to share the panel and derivative cultures with the community. Finally, we will take advantage of improved single-cell technologies to characterize the dispersion and robustness associated with single-cell gene regulation and identify genetic mechanisms that underlie the regulation of gene regulatory noise.


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 = $0 )
2025	2024	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Biomedical Research and Research Training	000	6	11/7/2024	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $534,228 )
2024	2024	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Biomedical Research and Research Training	000	6	7/5/2024	COMPETING CONTINUATION	$534,228
														Subtotal = $534,228

Issue Date FY: 2023 ( Subtotal = $513,942 )
2023	2023	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Biomedical Research and Research Training	000	5	5/9/2023	NON-COMPETING CONTINUATION	$513,942
														Subtotal = $513,942

Issue Date FY: 2022 ( Subtotal = $513,942 )
2022	2022	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Biomedical Research and Research Training	000	4	5/24/2022	NON-COMPETING CONTINUATION	$513,942
														Subtotal = $513,942

Issue Date FY: 2021 ( Subtotal = $513,942 )
2021	2021	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Biomedical Research and Research Training	000	3	5/14/2021	NON-COMPETING CONTINUATION	$513,942
														Subtotal = $513,942

Issue Date FY: 2020 ( Subtotal = $513,942 )
2020	2020	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Biomedical Research and Research Training	000	2	5/16/2020	NON-COMPETING CONTINUATION	$513,942
														Subtotal = $513,942

Issue Date FY: 2019 ( Subtotal = $68,422 )
2019	2019	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Biomedical Research and Research Training	000	1	5/16/2019	NEW	$68,422
														Subtotal = $68,422

Grand Total All Awards = $2,658,418

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Characterizing and Understanding Variation in Gene Regulatory Mechanisms Within and Between Species

Award Number: R35GM131726

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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