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Dissecting Inflammatory and Immune Mechanisms Driving Ovarian Tissue Aging

Award Number: R01AG099844
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/15/2026
PERIOD OF PERFORMANCE END DATE: 02/28/2031

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Dissecting Inflammatory and Immune Mechanisms Driving Ovarian Tissue Aging - PROJECT SUMMARY/ABSTRACT Age-related ovarian dysfunction is accompanied by sustained, low-grade inflammation and maladaptive immune activation—characterized by immune cell accumulation, fibrosis, and multinucleated giant cell (MNGC) formation. These pathological features arise before reproductive senescence and precede inflammatory remodeling seen during aging in other tissues. Yet, the cellular drivers, signaling mechanisms, and intercellular communication underlying these inflammatory responses in ovarian tissue remain largely unknown. This proposal focuses on how innate and adaptive immune components contribute to chronic, low-grade inflammation and structural tissue remodeling in the ovary. We aim to define how immune-tissue crosstalk promotes fibrosis, immune cell accumulation and activation, and other aging hallmarks. Our preliminary data identified proinflammatory programs that are activated in a cell-type-specific manner during early ovarian aging, implicating granulosa cells, tissue-resident macrophages (TRMs), and Type 17 T cells in a cascade of non-resolving inflammatory signaling. Our central hypothesis is that granulosa cell–intrinsic NF-κB activation initiates a feed- forward inflammatory loop with TRMs and Type 17 T cells, resulting in tissue fibrosis, MNGC formation, and immune-mediated ovarian dysfunction. We will test this hypothesis through the following mechanistic aims: Aim 1: Determine whether NF-κB signaling in granulosa cells orchestrates paracrine immune activation. We predict that NF-κB activation initiates proinflammatory signaling that promotes the recruitment and activation of TRMs and Type 17 T cells. Conditional ablation of NF-κB in granulosa cells will allow us to isolate its role in initiating immune crosstalk and downstream fibrotic pathology. Aim 2: Define the functional role of TRMs in sustaining ovarian inflammation. We hypothesize that ovarian TRMs act as critical amplifiers of age-related inflammatory responses and tissue remodeling. Using targeted macrophage depletion strategies, we will assess whether TRMs are required for T cell expansion, fibrotic signaling, and MNGC formation. Aim 3: Characterize Type 17 T cells in the aging ovary and their contribution to fibrotic remodeling. Type 17 T cells have been implicated in chronic inflammation across tissues, but their role in ovarian aging is unexplored. We will assess their phenotype, spatial localization, and impact on inflammatory signaling and fibrotic changes following targeted depletion. This research will also determine the temporal hierarchy of immune activation in ovarian aging and how intercellular inflammatory signaling evolves across the tissue. By delineating cell-type-specific contributions to chronic inflammation, this work will also provide a blueprint for understanding immune-mediated aging in other tissues. Rather than focusing on reproductive endpoints, we use the ovary as a model of immune-driven fibrosis and sterile inflammation—processes central to aging in multiple organs. Findings from this work will identify novel, immunological targets for intervention that could be used to delay ovarian aging and benefit overall health.


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 = $711,479 )
2026	2026	OKLAHOMA MEDICAL RESEARCH FOUNDATION	825 NE 13TH ST	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Aging Research	002	1	4/21/2026	NEW	$0
2026	2026	OKLAHOMA MEDICAL RESEARCH FOUNDATION	825 NE 13TH ST	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Aging Research	000	1	3/6/2026	NEW	$663,248
2026	2026	OKLAHOMA MEDICAL RESEARCH FOUNDATION	825 NE 13TH ST	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Aging Research	001	1	3/16/2026	NEW	$48,231
														Subtotal = $711,479

Grand Total All Awards = $711,479

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Dissecting Inflammatory and Immune Mechanisms Driving Ovarian Tissue Aging

Award Number: R01AG099844

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/15/2026

PERIOD OF PERFORMANCE END DATE: 02/28/2031

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