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Cell-type specific role of melanocortin 4 receptor in inflammation and cognition with aging

Award Number: R21AG093578
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2025
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Cell-type specific role of melanocortin 4 receptor in inflammation and cognition with aging - Low-grade, chronic inflammation (“inflammaging”) is a pillar of aging, with neuroinflammation in the hippocampus associated with decreased cognitive ability and decreased lifespan. Feeding rodents a high fat diet (HFD) mimics the neuroinflammation, shortened lifespan, and compromised cognitive ability similar to what is seen with aging. However, the molecular mechanisms responsible for central inflammaging remain elusive despite their crucial role in health- and lifespan. Melanocortins (MCs) are neuropeptides that have major roles in body weight homeostasis but are also anti-inflammatory and increase cognition, and decrease amyloid beta levels and neurodegeneration. Endogenous MC expression decreases with age, providing a plausible mechanism to explain increased obesity, decreased cognition, and increased inflammation with aging. MCs decrease inflammation by blocking activity in the same inflammatory pathways and production of mediators of inflammation. MCs act on melanocortin 4 receptors (MC4R) found predominantly in the brain on both neurons and astrocytes, with little expression in the periphery. Our preliminary data show that administration of an MC4R agonist to 18-month-old mice decreases inflammation in the hippocampus and increases cognition. However, it isn’t known if these beneficial effects of MC4R agonists are mediated through astrocytic or neuronal populations. Our lab has also found that deletion of MC4R only on astrocytes in the hippocampus is sufficient to induce inflammation measured by an increase in microglial activation. Surprisingly, development of MC agonists as an intervention to slow aging is largely unexplored, likely due to a lack of understanding of how MCs mediate these effects at a cell-type specific level as there is no data linking astrocytic MC4R to inflammation in aged populations. Our objective is to define the role of astrocytic and neuronal MC4R populations in inflammaging both molecularly (astrocyte reactivity, microglial activation, synaptic health, and inflammatory pathways) and behaviorally (cognition and reward learning). We hypothesize that astrocytic, but not neuronal populations of MC4R mediate age-induced hippocampal inflammation. We will use a combination of genetic mouse model with a transcriptional blocker for MC4R with viral vector-mediated excision of the transcriptional blocker to rescue MC4R expression in a site- and cell-type specific manner. We will then administer the MC4R agonist setmelanotide to activate the receptor population to determine if MC4R agonist activity on astrocytes and/or neurons in the hippocampus is able to prevent the development of HFD- induced inflammation and cognitive dysfunction (Aim 1) or to reverse already existing neuroinflammation and cognitive dysfunction in older mice that have been on a HFD and already have inflammation and cognitive dysfunction (Aim 2). These studies will establish the cell type(s) responsible for the positive behavioral effects and anti-inflammatory action of MC4R agonists in a HFD-based aging model. This is essential for informed design of therapeutics to decrease neuroinflammation and increase healthspan.


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	2026	OKLAHOMA MEDICAL RESEARCH FOUNDATION	825 NE 13TH ST	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Aging Research	001	2	3/9/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$253,666
2026	2025	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Aging Research	000	1	3/9/2026	NEW	-$253,666
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $393,250 )
2025	2025	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Aging Research	000	1	5/16/2025	NEW	$393,250
														Subtotal = $393,250

Grand Total All Awards = $393,250

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Cell-type specific role of melanocortin 4 receptor in inflammation and cognition with aging

Award Number: R21AG093578

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2025

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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