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Influence of Particulate Matter on Fetal Mitochondrial Programming

Award Number: R01ES034628
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/07/2023
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Influence of Particulate Matter on Fetal Mitochondrial Programming - PROJECT SUMMARY The distribution of engineered nanomaterials (ENM) in consumer products, manufacturing processes and clinical diagnostics is rising rapidly, despite our limited understanding of their impacts on human health. ENM exposure is of particular concern during fetal development and it can influence susceptibility to pathological insults later in life. Mitochondria play an important role in fetal developmental and they can be impacted by environmental conditions, which has led to the novel concept of mitochondrial programming. Epigenetic changes are important determinants of mitochondrial programming, as they influence the organelle's proteomic make-up, which is responsible for its structure, function and redox balance. Nevertheless, mitochondrial programming in the context of development is understudied. Our laboratory made the initial observation that maternal ENM inhalation exposure causes cardiac contractile dysfunction and disruption to mitochondrial bioenergetics in the developing fetus. These effects were sustained into adulthood. We also reported that maternal ENM inhalation exposure increases epigenetic methylation of mRNAs in the fetal heart. MRNA methylation occurs primarily to adenosine leading to N6-methyladenosine (m6A), and to a lesser extent to cytosine, leading to 5-methylcytosine (m5C). The preliminary data in this grant application suggest that maternal ENM inhalation exposure influences fetal cardiac mitochondrial programming by enhancing oxidant production and mitochondrial dysfunction, but it is unclear whether this is mechanistically linked by epigenetic methylation to nuclear genome-encoded mitochondrial mRNAs and loss of mitochondrial proteins. The proposed studies focus on this gap in knowledge and they are designed to determine whether maternal ENM inhalation exposure negatively influences mitochondrial programming in the fetal heart and the susceptibility to future cardiac pathological insult, through an oxidant driven mechanism. The studies address this specific need, as they will identify mechanisms driving fetal mitochondrial dysfunction resulting from maternal ENM inhalation exposure as well as the susceptibility to a secondary cardiac pathological insult that occurs later in life. The central hypothesis being tested is that maternal ENM inhalation exposure epigenetically reprograms fetal cardiac mitochondria through an oxidant- driven mechanism that results in enhanced susceptibility to a secondary cardiovascular insult at adulthood. The objectives of this application are to determine the influence of maternal ENM inhalation exposure and the impact of enhanced oxidant scavenging on (1) fetal cardiac mitochondrial programming that influence mitochondrial structure, function and redox balance; (2) fetal cardiac epigenetic methylation of nuclear genome-encoded mRNAs that encode for mitochondrial proteins; and (3) the susceptibility to a secondary cardiovascular insult at adulthood. Completion of these studies is expected to provide fundamental mechanistic insight regarding fetal mitochondrial programming in maternal exposure models and the susceptibility to future cardiac pathologies.


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 = $342,000 )
2025	2025	WEST VIRGINIA UNIVERSITY RESEARCH CORPORATION	886 CHESTNUT RIDGE ROAD	MORGANTOWN	WV	26505	MONONGALIA	USA	Environmental Health	000	3	4/4/2025	NON-COMPETING CONTINUATION	$342,000
														Subtotal = $342,000

Issue Date FY: 2024 ( Subtotal = $342,000 )
2024	2024	WEST VIRGINIA UNIVERSITY RESEARCH CORPORATION	886 CHESTNUT RIDGE ROAD	MORGANTOWN	WV	26505	MONONGALIA	USA	Environmental Health	000	2	4/24/2024	NON-COMPETING CONTINUATION	$342,000
														Subtotal = $342,000

Issue Date FY: 2023 ( Subtotal = $342,000 )
2023	2023	WEST VIRGINIA UNIVERSITY RESEARCH CORPORATION	886 CHESTNUT RIDGE ROAD	MORGANTOWN	WV	26505	MONONGALIA	USA	Environmental Health	000	1	7/6/2023	NEW	$342,000
														Subtotal = $342,000

Grand Total All Awards = $1,026,000

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Influence of Particulate Matter on Fetal Mitochondrial Programming

Award Number: R01ES034628

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/07/2023

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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