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Paternal stress epigenetic programming of offspring neurodevelopment

Award Number: R37MH108286
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Paternal stress epigenetic programming of offspring neurodevelopment - Parental lifetime exposures to perturbations such as stress, infection, malnutrition, and to advanced age have been linked with an increased risk for neurodevelopmental disorders in their children. While maternal insults during pregnancy can directly impact fetal development, the mechanisms by which paternal lifelong experiences can alter germ cell programming and affect offspring neurodevelopment are not known. However, transmission of these epigenetic marks to the next generation can significantly elevate disease risk, and if programmed into the germline can affect future generations as well. Using male stress experience as a model in which we can examine mechanisms involved in offspring neurodevelopmental programming, we found that paternal stress significantly altered offspring HPA stress axis regulation and reprogrammed the hypothalamus. Mechanistically, we identified 9 specific miRNAs in the mature sperm from stressed males that contributed to the offspring phenotype. Further, we were able to completely recapitulate the offspring phenotype by microinjection of these 9 miRNAs into fertilized zygotes. Using single-cell amplification technology, we were identified a novel role for these miRNAs to significantly affect post-fertilization embryo development, providing substantial evidence that sperm miRNAs are programmable by the environment and are able to transmit this information allowing for paternally directed embryo development. Therefore, our proposal will utilize our mouse model of paternal stress to examine: 1) the mechanisms whereby stress alters paternal germ cell miRNA that affect neurodevelopment and give rise to the offspring phenotype, 2) the transgenerational transmission of stress dysregulation to a second generation programmed by paternal stress and sperm miRNAs, and 3) the mechanism within the offspring brain that promotes the paternal stress phenotype through increased BBB permeability and repressive histone epigenetic 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: 2027 ( Subtotal = -$1,630 )
2027	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Mental Health Research Grants	000	12	10/14/2026	NON-COMPETING CONTINUATION	-$1,630
														Subtotal = -$1,630

Issue Date FY: 2024 ( Subtotal = $689,078 )
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Mental Health Research Grants	000	12	5/30/2024	NON-COMPETING CONTINUATION	$689,078
														Subtotal = $689,078

Issue Date FY: 2023 ( Subtotal = $691,850 )
2023	2023	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Mental Health Research Grants	002	11	5/30/2023	NON-COMPETING CONTINUATION	$689,078
2023	2022	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Mental Health Research Grants	000	9	5/9/2023	NON-COMPETING CONTINUATION	-$428,047
2023	2022	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Mental Health Research Grants	003	9	8/18/2023	NON-COMPETING CONTINUATION	$3,321
2023	2022	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Mental Health Research Grants	004	10	8/18/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$3,321
2023	2022	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Mental Health Research Grants	001	10	5/10/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$430,819
2023	2022	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Mental Health Research Grants	005	9	9/27/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $691,850

Issue Date FY: 2022 ( Subtotal = $684,647 )
2022	2022	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Mental Health Research Grants	000	9	6/30/2022	NON-COMPETING CONTINUATION	$684,647
														Subtotal = $684,647

Issue Date FY: 2021 ( Subtotal = $684,647 )
2021	2021	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Mental Health Research Grants	001	8	6/16/2021	NON-COMPETING CONTINUATION	$684,647
2021	2019	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Mental Health Research Grants	000	6	6/12/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $684,647

Issue Date FY: 2020 ( Subtotal = $636,646 )
2020	2020	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Mental Health Research Grants	000	7	4/23/2020	EXTENSION WITH OR WITHOUT FUNDS	$636,646
														Subtotal = $636,646

Issue Date FY: 2019 ( Subtotal = $514,261 )
2019	2019	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Mental Health Research Grants	000	6	4/23/2019	NON-COMPETING CONTINUATION	$514,261
														Subtotal = $514,261

Issue Date FY: 2018 ( Subtotal = $528,980 )
2018	2018	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Mental Health Research Grants	005	5	5/31/2018	NON-COMPETING CONTINUATION	$528,980
2018	2017	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Mental Health Research Grants	003	3	2/12/2018	NON-COMPETING CONTINUATION	-$181,652
2018	2017	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Mental Health Research Grants	001	4	11/13/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$380,816
2018	2017	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Mental Health Research Grants	000	3	11/13/2017	NON-COMPETING CONTINUATION	-$380,816
2018	2017	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Mental Health Research Grants	004	4	2/12/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$252,596
2018	2016	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Mental Health Research Grants	002	2	2/12/2018	NON-COMPETING CONTINUATION	-$70,944
														Subtotal = $528,980

Issue Date FY: 2017 ( Subtotal = $562,468 )
2017	2017	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Mental Health Research Grants	000	3	5/19/2017	NON-COMPETING CONTINUATION	$562,468
														Subtotal = $562,468

Issue Date FY: 2016 ( Subtotal = $570,468 )
2016	2016	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Mental Health Research Grants	000	2	5/31/2016	NON-COMPETING CONTINUATION	$570,468
														Subtotal = $570,468

Grand Total All Awards = $5,561,415

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Paternal stress epigenetic programming of offspring neurodevelopment

Award Number: R37MH108286

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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