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Site 3/3, Understanding PTSD through Postmortem Targeted Brain Multiomics

Award Number: R01MH117292
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/25/2018
PERIOD OF PERFORMANCE END DATE: 02/28/2030

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Site 3/3, Understanding PTSD through Postmortem Targeted Brain Multiomics - Project Summary/Abstract Post-traumatic stress disorder (PTSD) and major depressive disorder (MDD) are prevalent and disabling. Alt- hough trauma exposure is common and most trauma victims recover, the ~10% who develop chronic PTSD continue to have debilitating symptoms of re-experiencing, avoidance and hyperarousal as well as depression symptoms. It is critical to identify the underlying neurobiology of PTSD susceptibility and to further understand underlying differences between PTSD and MDD. Despite their clinical importance, there are limited human biol- ogy-focused postmortem brain studies of well-matched PTSD and MDD cases and controls to leverage the fact that these are well understood Psychiatric Disorders in terms of neural circuit regulation. This Competitive Re- newal utilizes a Collaborative R01 mechanism across 3-sites (University of Texas (1), Lieber Institute for Brain Development (2), and McLean Hospital (3)), to extend a postmortem, multi-omic study of brains (PTSD Brainom- ics Project), building on progress from data from the initial grant period with 300 additional new subjects in this proposal across the 3 diagnostic categories of 1) PTSD, 2) MDD, and 3) ‘neurotypical’ controls. We will focus on targeted brain regions with known differential association with PTSD risk as a function of identified intermediate phenotypes, including amygdala, hippocampus, and dorsal raphe nucleus. We will conduct DNA genotyping (LIBD) and bulk-tissue DNA methylation and whole-genome bisulfite sequencing (on a subset), RNA-sequencing and protein expression across brain regions. We will also perform single nucleus (sn) Multiome-sequencing that combines snRNAseq and snATACseq to expand interpretation of the bulk multiomic data and spatial tran- scriptomics on select brain samples. Our new 900 samples from 300 new subjects will also support metaanalyses with prior samples for 1800 total brain samples from 600 total subjects. We will aim to investigate the roles of: 1) gene expression and alternative splicing in PTSD/MDD and trauma exposure in relation to upstream epigenetic regulation and downstream (phosphor)protein expression; 2) gene expression and chromatin accessibility in individual brain cells and spatial organization of molecular alterations in PTSD/MDD and trauma exposure; 3) polygenic risk and putative causal variants in PTSD/MDD and trauma exposed brains, and 4) to utilize systems biology, factor analysis and deep learning to understand traumatic stress related outcomes. We will use state- of-the-art statistical modeling, combined with rich psychological and biological phenotype measurements to de- termine disease-associated networks across brain regions and molecular pathways. This novel, integrated, and impactful linked R01 proposal will lead to identification of unknown trauma-associated genes and proteins, ncRNAs, and epigenetic marks in trauma related disorders and identify novel therapeutic targets. It will also expand understanding of cell-type-specific multiomic regulation. Our strategy has the potential to help redefine psychobiological subtypes of PTSD and reduce the burden of chronic PTSD.


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 = $1,020,847 )
2025	2025	THE MCLEAN HOSPITAL CORPORATION	115 MILL ST	BELMONT	MA	02478	MIDDLESEX	USA	Mental Health Research Grants	000	6	5/27/2025	COMPETING CONTINUATION	$1,020,847
														Subtotal = $1,020,847

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	THE MCLEAN HOSPITAL CORPORATION	115 MILL ST	BELMONT	MA	02478	MIDDLESEX	USA	Mental Health Research Grants	000	5	7/19/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $594,777 )
2022	2022	MCLEAN HOSPITAL CORPORATION, THE	115 MILL ST	BELMONT	MA	02478	MIDDLESEX	USA	Mental Health Research Grants	000	5	4/29/2022	NON-COMPETING CONTINUATION	$594,777
														Subtotal = $594,777

Issue Date FY: 2021 ( Subtotal = $602,977 )
2021	2021	MCLEAN HOSPITAL CORPORATION, THE	115 MILL ST	BELMONT	MA	02478	MIDDLESEX	USA	Mental Health Research Grants	000	4	5/19/2021	NON-COMPETING CONTINUATION	$602,977
														Subtotal = $602,977

Issue Date FY: 2020 ( Subtotal = $602,977 )
2020	2020	MCLEAN HOSPITAL CORPORATION, THE	115 MILL ST	BELMONT	MA	02478	MIDDLESEX	USA	Mental Health Research Grants	000	3	5/6/2020	NON-COMPETING CONTINUATION	$602,977
														Subtotal = $602,977

Issue Date FY: 2019 ( Subtotal = $611,177 )
2019	2019	MCLEAN HOSPITAL CORPORATION, THE	115 MILL ST	BELMONT	MA	02478	MIDDLESEX	USA	Mental Health Research Grants	000	2	5/1/2019	NON-COMPETING CONTINUATION	$611,177
														Subtotal = $611,177

Issue Date FY: 2018 ( Subtotal = $627,177 )
2018	2018	MCLEAN HOSPITAL CORPORATION, THE	115 MILL ST	BELMONT	MA	02478	MIDDLESEX	USA	Mental Health Research Grants	000	1	7/25/2018	NEW	$627,177
														Subtotal = $627,177

Grand Total All Awards = $4,059,932

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Site 3/3, Understanding PTSD through Postmortem Targeted Brain Multiomics

Award Number: R01MH117292

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/25/2018

PERIOD OF PERFORMANCE END DATE: 02/28/2030

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