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Transduction of Psychological Stress into Systematic Inflammation by Mitochondrial DNA Signaling

Award Number: R01MH119336
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2019
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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Transduction of Psychological Stress into Systematic Inflammation by Mitochondrial DNA Signaling - PROJECT SUMMARY Systemic inflammation is believed to contribute to the damaging health effects of psychological stress. In the laboratory setting, a single acute bout of socioevaluative stress leads to a delayed elevation of pro- inflammatory cytokines in healthy adults. However, the biological mechanisms by which psychological stress is transduced into inflammation is not well understood. A cellular component known to contribute to stress signaling is the mitochondrion – a bacteria-derived organelle with its own genome, the mitochondrial DNA (mtDNA). Recent evidence has demonstrated that various stressors induce the release of mitochondria- derived signaling molecules, or mitokines. Mitokines travel systemically and modulate central physiological processes, including immune cell function and the production of pro-inflammatory cytokines. One key mitokine is circulating cell-free mtDNA (ccf-mtDNA), which arises from mitochondrial extrusion of mtDNA, is recognized by the toll-like receptor 9 (TLR-9), and leads to pro-inflammatory cytokine production in animal and human cells. Our preliminary data showed that ccf-mtDNA release, but not ccf-nuclear DNA, is acutely induced following a brief experimental psychological stress in humans. Thus, we suggest that ccf-mtDNA may be a missing link in the stress-inflammation cascade. In parallel, imaging and molecular studies on cellular systems suggests that ccf-mtDNA may be rapidly induced by primary neuroendocrine stress mediators, including glucocorticoids. This proposal will use an experimental socio-evaluative stress task, counterbalanced with a control no-stress visit for each participant, to map the kinetics of reactivity and recovery in ccf-mtDNA and other stress mediators in healthy women and men. Aim 1 will establish: i) the magnitude and kinetics of ccf- mtDNA release; ii) the specificity of this response compared to nuclear DNA; iii) examine potential sex differences in this process; and iv) statistically test ccf-mtDNA as a mediator of the subsequent increase in pro- inflammatory cytokines. In Aim 2, cellular and molecular studies will determine: i) whether primary glucocorticoid and catecholamine stress hormones are sufficient to trigger ccf-mtDNA release in primary human cultured cells and isolated leukocytes; ii) image in living cells mtDNA release in response to stress signaling; and iii) document physical changes in mtDNA structure that contribute to ccf-mtDNA release. Finally, Aim 3 will establish: i) the capacity of ccf-mtDNA from peak ccf-mtDNA serum to activate cytokine production in target cells; ii) the structural form and accessibility of ccf-mtDNA in human serum (from Aim 1); and iii) the dependency on TLR-9 for immune activation. Overall, these studies will contribute mechanistic evidence for a novel mitochondria-mediated mechanisms for transducing stress into inflammation in humans. Outcomes from this work will identify new potential targets to improve stress-related mental health and inflammatory disorders.


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: 2026 ( Subtotal = $0 )
2026	2023	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC.	1051 RIVERSIDE DR	NEW YORK	NY	10032	NEW YORK	USA	Mental Health Research Grants	000	5	12/10/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $674,810 )
2023	2023	RESEARCH FOUNDATION FOR MENTAL HYGIENE INC	1051 RIVERSIDE DR	NEW YORK	NY	10032	NEW YORK	USA	Mental Health Research Grants	000	5	3/9/2023	NON-COMPETING CONTINUATION	$674,810
2023	2023	RESEARCH FOUNDATION FOR MENTAL HYGIENE INC	1051 RIVERSIDE DR	NEW YORK	NY	10032	NEW YORK	USA	Mental Health Research Grants	001	5	8/7/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $674,810

Issue Date FY: 2022 ( Subtotal = $681,923 )
2022	2022	RESEARCH FOUNDATION FOR MENTAL HYGIENE INC	1051 RIVERSIDE DR	NEW YORK	NY	10032	NEW YORK	USA	Mental Health Research Grants	001	4	5/23/2022	NON-COMPETING CONTINUATION	$68,196
2022	2022	RESEARCH FOUNDATION FOR MENTAL HYGIENE INC	1051 RIVERSIDE DR	NEW YORK	NY	10032	NEW YORK	USA	Mental Health Research Grants	000	4	2/16/2022	NON-COMPETING CONTINUATION	$613,727
														Subtotal = $681,923

Issue Date FY: 2021 ( Subtotal = $652,967 )
2021	2021	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC.	1051 RIVERSIDE DR	NEW YORK	NY	10032	NEW YORK	USA	Mental Health Research Grants	000	3	2/23/2021	NON-COMPETING CONTINUATION	$652,967
														Subtotal = $652,967

Issue Date FY: 2020 ( Subtotal = $683,563 )
2020	2020	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC.	1051 RIVERSIDE DR	NEW YORK	NY	10032	NEW YORK	USA	Mental Health Research Grants	000	2	2/13/2020	NON-COMPETING CONTINUATION	$683,563
														Subtotal = $683,563

Issue Date FY: 2019 ( Subtotal = $701,505 )
2019	2019	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC.	1051 RIVERSIDE DR	NEW YORK	NY	10032	NEW YORK	USA	Mental Health Research Grants	000	1	4/23/2019	NEW	$701,505
														Subtotal = $701,505

Grand Total All Awards = $3,394,768

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Transduction of Psychological Stress into Systematic Inflammation by Mitochondrial DNA Signaling

Award Number: R01MH119336

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2019

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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