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Characterization of endocrine signaling and RNAi pathways as mechanisms regulating environmental programming in C. elegans

Award Number: R01GM129135
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: 06/17/2019
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Characterization of endocrine signaling and RNAi pathways as mechanisms regulating environmental programming in C. elegans - Increasing evidence suggests that fetal and childhood experiences impact adult disease in humans through changes in tissue-specific gene expression states and sustained altered function of the neuroendocrine HPA axis. However, the molecular pathways by which environmental cues experienced in utero or early childhood result in long-lasting effects associated with adult disease, and how they can be inherited over generations, are not well understood. Caenorhabditis elegans nematodes provide a unique animal model system in which to explore the mechanisms of environmental programming of gene expression due to early experience. Although adult animals that experienced environmental stress early in development appear grossly identical to animals that experienced favorable conditions, these adults retain a cellular memory of their environmental history that is manifested by changes in gene expression and fertility that are distinct for the particular stress experienced. Animals that experienced early-life starvation exhibited decreased fertility compared to controls, which is dependent upon the upregulation of conserved endocrine signaling pathways and the CSR-1 RNAi pathway. Interestingly, these endocrine signaling pathways, steroid hormone signaling and fatty acid metabolism, are also upregulated in long-lived animals lacking a germ line. In addition, the reduced fertility phenotype of starvation-stressed animals is also inherited for at least two generations via the HRDE-1 RNAi pathway. The overall goal of this proposal is to investigate how pathways that can promote longevity in germline-less animals can also modulate reproduction in animals that experienced nutritional stress. The specific aims of this proposal include: 1) investigate the roles of steroid signaling and fatty acid metabolism in the regulation of fertility after early-life starvation. This aim proposes genetic and biochemical experiments to test the hypothesis that DAF-12/NHR acts as a “fat sensor” to modulate germ line production based on levels of stored fat by directly regulating gene(s) with functions in promoting the onset of germline proliferation. 2) Using biochemical and developmental genetics experiments, test whether the increased fatty acid metabolism in csr-1 hypomorph adults is due to direct regulation of fat genes by CSR-1 in the intestine, or an indirect effect of reduced fertility in the csr-1 hypomorph, as germ line defects may trigger these pathways. 3) Determine the mechanisms of inheritance for reduced fertility in progeny of animals that experienced nutritional stress. Experiments will test whether steroid signaling and fatty acid metabolism genes are also upregulated in F1 progeny. HRDE-1 associated siRNAs will also be deep sequenced in the progeny to identify target genes contributing to the reduced fertility phenotype. Together, these experiments will investigate how pathways that promote somatic longevity in germline-less animals can also modulate fertility due to early life starvation, and how RNAi pathways contribute to inheritance of metabolic programming.


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	2023	SYRACUSE UNIVERSITY	900 S CROUSE AVE	SYRACUSE	NY	13244	ONONDAGA	USA	Biomedical Research and Research Training	000	5	6/2/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $300,000 )
2023	2023	SYRACUSE UNIVERSITY	900 S CROUSE AVE	SYRACUSE	NY	13244	ONONDAGA	USA	Biomedical Research and Research Training	000	5	5/11/2023	NON-COMPETING CONTINUATION	$300,000
														Subtotal = $300,000

Issue Date FY: 2022 ( Subtotal = $300,000 )
2022	2022	SYRACUSE UNIVERSITY	900 S CROUSE AVE STE 620	SYRACUSE	NY	13244	ONONDAGA	USA	Biomedical Research and Research Training	000	4	5/17/2022	NON-COMPETING CONTINUATION	$300,000
														Subtotal = $300,000

Issue Date FY: 2021 ( Subtotal = $300,000 )
2021	2021	SYRACUSE UNIVERSITY	900 S CROUSE AVE STE 620	SYRACUSE	NY	13244	ONONDAGA	USA	Biomedical Research and Research Training	000	3	5/24/2021	NON-COMPETING CONTINUATION	$300,000
														Subtotal = $300,000

Issue Date FY: 2020 ( Subtotal = $300,000 )
2020	2020	SYRACUSE UNIVERSITY	900 S CROUSE AVE STE 620	SYRACUSE	NY	13244	ONONDAGA	USA	Biomedical Research and Research Training	000	2	5/22/2020	NON-COMPETING CONTINUATION	$300,000
														Subtotal = $300,000

Issue Date FY: 2019 ( Subtotal = $300,000 )
2019	2019	SYRACUSE UNIVERSITY	900 S CROUSE AVE STE 620	SYRACUSE	NY	13244	ONONDAGA	USA	Biomedical Research and Research Training	000	1	6/13/2019	NEW	$300,000
														Subtotal = $300,000

Grand Total All Awards = $1,500,000

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Characterization of endocrine signaling and RNAi pathways as mechanisms regulating environmental programming in C. elegans

Award Number: R01GM129135

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: 06/17/2019

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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