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Coupling between circadian rhythms and redox signaling in stem cell differentiation and adult neurogenesis

Award Number: F32MH125600
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/01/2020
PERIOD OF PERFORMANCE END DATE: 11/30/2023

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Coupling between circadian rhythms and redox signaling in stem cell differentiation and adult neurogenesis - Project Summary Circadian rhythms are necessary to coordinate the timing of key behavioral and physiological processes in mammals [1-3]. However, while our understanding of the function of circadian clock genes in embryonic development is rapidly advancing [4-6], the molecular mechanisms through which these rhythms emerge during stem cell differentiation remain elusive [7]. Recently, signaling by reactive oxygen species (redox signaling) has emerged as an essential link between cellular metabolism and circadian rhythms in adult function [8, 9]. Signaling from the pentose phosphate pathway through production of redox cofactor NADPH is an important regulator of transcriptional oscillations, influencing the expression of core circadian clock genes through the redox-sensitive transcription factor NRF2 [10]. NRF2 is a crucial regulator of embryonic stem cell pluripotency and self-renewal, but whether redox signaling contributes to the development of circadian rhythms in differentiating stem cells remains completely unexplored [11]. Using fluorescent reporters of the hydrogen peroxide and Per2 expression, we propose to simultaneously visualize reactive oxygen species and circadian rhythms in single cells for the first time. By combining this novel model system with CRISPR/Cas9-mediated genome editing approaches, we will causally test the role of redox signaling in the development of circadian rhythms in human induced pluripotent stem cells undergoing directed differentiation to glutamatergic neurons. Using adult hippocampal neurogenesis as an in vivo model system for neuronal differentiation, we will further explore the function of redox-circadian coupling in coordinating the sequential development and circuit integration of adult-born granule cells. The long-term objective of this proposal is to create a novel model system to explore the mechanisms through which reciprocal interaction between redox and circadian transcription factor networks direct the proper sequential timing of development. While the current proposal seeks to investigate how redox-circadian coupling drives the differentiation of pluripotent and adult stem cells, we aim to describe a general paradigm for the coordination of metabolism, cell division, and stem cell homeostasis in health and disease. Hypothesis: We hypothesize that redox signaling drives the development of circadian rhythms in stem cells following the loss of pluripotency, and that reciprocal regulation between redox signaling and circadian rhythms drives the cellular maturation. We predict that disrupting redox-circadian coupling in adult neural stem cells through acute Nrf2 knockout will induce cell division and differentiation, but hinder the development of circadian rhythms and normal maturation of adult-born granule cells. We will test this hypothesis in the following aims: Aim 1: Causally link redox signaling to circadian rhythm development in human induced pluripotent stem cells Aim 2: Determine impact of Nrf2 KO-mediated disruption of redox-circadian coupling on adult neurogenesis


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 = -$6,854 )
2024	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Mental Health Research Grants	000	3	9/23/2024	NON-COMPETING CONTINUATION	-$6,854
														Subtotal = -$6,854

Issue Date FY: 2023 ( Subtotal = $74,080 )
2023	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Mental Health Research Grants	000	3	11/23/2022	NON-COMPETING CONTINUATION	$72,582
2023	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Mental Health Research Grants	001	3	3/7/2023	NON-COMPETING CONTINUATION	$1,498
														Subtotal = $74,080

Issue Date FY: 2022 ( Subtotal = $72,174 )
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Mental Health Research Grants	001	2	7/18/2022	NON-COMPETING CONTINUATION	$1,180
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Mental Health Research Grants	000	2	11/11/2021	NON-COMPETING CONTINUATION	$70,994
														Subtotal = $72,174

Issue Date FY: 2020 ( Subtotal = $69,554 )
2020	2020	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Mental Health Research Grants	000	1	9/11/2020	NEW	$69,554
														Subtotal = $69,554

Grand Total All Awards = $208,954

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Coupling between circadian rhythms and redox signaling in stem cell differentiation and adult neurogenesis

Award Number: F32MH125600

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/01/2020

PERIOD OF PERFORMANCE END DATE: 11/30/2023

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