The immunobiological mechanisms of depression in perimenopause

Active Project Grant Awarded Last action

Award ID
R01MH139201
Recipient
Awarding agency
Obligated
$2,604,519

Award facts

Assistance listing
93.242 Mental Health Research Grants
Completion date 38% complete
Place of performance
Wyoming, MI 49503, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
This project aims to identify immunobiological mechanisms underlying the development of depression during the perimenopause, in response to the nimh funding opportunity "mood and psychosis symptoms during the menopause transition". During the perimenopause, the risk for recurrence of depression is increased 13-fold among women who previously had depression. Moreover, perimenopause overlaps with the age span exhibiting the highest suicide rate for women. The perimenopause can last for several years and starts when estrogen and progesterone levels begin to fluctuate, gradually declining. SEX hormones are powerful modulators of the immune response and we therefore propose that changes in lymphocytes play a central role in depression during this time. Notably, our previous work has demonstrated deficient regulatory T-cell responses in women with post- partum depression and identified a specific pro-inflammatory profile (composed of cytokines and tryptophan metabolites) that predicts depression during pregnancy. Importantly, our new pilot data derived from women with severe depression in the perimenopausal age span reveals alterations in tryptophan metabolites that control T- cell responses as well as in the methylation of genes involved in T-cell fate and chromatin remodeling. Taken together, these data support our hypothesis that the perimenopausal hormonal shifts induce a pro-inflammatory state, regulated by chromatin modifications in T-cells, that triggers depression in vulnerable women. To test this hypothesis, we will enroll 150 perimenopausal women in a multi-site study to: 1) determine plasma tryptophan metabolite and cytokine patterns in perimenopausal depression; 2) define epigenetic mechanisms in lymphocytes that confer vulnerability to developing depression in perimenopause; and 3) identify inflammatory and metabolic markers that normalize in a subset of 60 women recovering from depression (RE-assessed 8 weeks after their initial visit), either treated with hormonal substitution therapy or untreated. We will undertake careful clinical diagnostics and confirm perimenopausal status using established criteria. In all participants, we will quantify plasma tryptophan metabolites, cytokines, and SEX hormones. We will also define peripheral immune cell populations and determine changes in DNA-methylation, chromatin accessibility and gene expression in naïve T-cells. Finally, we will test the functional response to inflammatory stimulation in cultured lymphocytes derived from the same women. We expect that women with perimenopausal depression will exhibit reduced levels of immunoregulatory tryptophan metabolites and signs of peripheral inflammation as well as differences in transcriptional regulation in lymphocytes. We predict that these distinct inflammatory responses will be linked to the development of depression. We also expect improvement of depressive symptoms and reversal of immunobiological markers in women receiving hormonal therapy. We envision that our project will lead to an improved understanding of the molecular underpinnings of depression during perimenopause, aiding the future identification of biomarkers of women at risk as well as the development of more effective treatments.

Transactions

Action Obligated Date
Amendment $765,613
Amendment $919,453
Original award $919,453

Subawards

Subrecipient Amount Awarded
Western Michigan University Homer Stryker M.d. School Of Medicine Participate in design and oversight of the study as a whole in collaboration with other MPIs. Oversee the recruitment and querying of any data related to… $113,296
Weill Medical College Of Cornell University This subcontract will support work conducted by Multi-PD/PI Dr. Lauren Osborne and her laboratory at Weill Cornell Medicine (WCM). The WCM team will be… $152,550
Pine Rest Christian Mental Health Services Recruit and enroll study participants over the course of the project from Pine Rest Christian Mental Health Services treatment settings. The team will manage… $88,234
Pine Rest Christian Mental Health Services Recruit approximately 50-65 study subjects over 4 years from Pine Rest Christian Mental Health Services treatment centers including inpatient/partial… $98,472
Western Michigan University Homer Stryker M.d. School Of Medicine Participate in design and oversight of the study as a whole in collaboration with other MPIs. Oversee the recruitment and querying of any data related to… $126,037
Weill Medical College Of Cornell University This subcontract will cover work carried out by Multi-PD/PI Dr. Lauren Osborne and her laboratory at Weill Cornell Medicine (WCM). WCM will recruit… $169,500

Quick answers

Who received award R01MH139201?

R01MH139201 was awarded to Van Andel Research Institute by National Institute of Mental Health (National Institutes of Health) on December 20, 2024.

How much is award R01MH139201 worth?

$2,604,519 has been obligated on R01MH139201.

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