Monday, June 30, 2025 6/30/2025

GOAT-mediated ghrelin deregulation and hippocampal pathology in Alzheimer's Disease

Award Number: R01AG059753
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2018
PERIOD OF PERFORMANCE END DATE: 11/30/2029

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GOAT-mediated ghrelin deregulation and hippocampal pathology in Alzheimer's Disease - Project Summary: Hippocampal lesions constitute a characteristic brain pathology underlying memory loss in both familial and sporadic Alzheimer’s disease (AD). Ghrelin, a stomach-produced, acylated peptide hormone, is the endogenous agonist of growth hormone secretagogue receptor (GHSR, also known as ghrelin receptor). In addition to the importance of the ghrelin system to systemic energy homeostasis, ghrelin passes the blood-brain-barrier (BBB) to elicit hippocampal GHSR signaling for the modulation of hippocampal synaptic activity. In our last funding period, we have determined the contribution of amyloid beta (Aβ)-induced GHSR deactivation to the development of hippocampal synaptic failure and cognitive deficits in AD-related conditions. Interestingly, in contrast to decreased availability of functional hippocampal GHSR, we also observed a paradoxical increase in circulating bioactive ghrelin in both AD patients and mouse models, including a mouse model of familial AD (5xFAD mice) and a mouse model of AD risk [human Aβ knockin (hAβ KI) mice, also referred to in the literature as a mouse model of late-onset sporadic AD], indicating that ghrelin overactivation is a phenotypic change in AD-relevant pathological settings. Although ghrelin is a neurotrophic peptide that stimulates GHSR to benefit hippocampal synaptic activity, administration of a synthetic ghrelin mimetic demonstrated no protection of cognitive function in 5xFAD mice and increased mouse mortality, echoing a previous failed large-scale clinical trial. Importantly, further experiments showed that persistent ghrelin exposure induced dose-dependent GHSR desensitization by promoting GHSR internalization. Together with the well-characterized detrimental impact of ghrelin deficiency on cognition, these findings highlight the importance of normal ghrelin regulation to GHSR function in hippocampal physiology and further implicate that disrupted ghrelin homeostasis due to overactivation is an undesirable pathological event promoting hippocampal GHSR dysfunction in AD paradigms. Ghrelin O- acyltransferase (GOAT) is the key enzyme that catalyzes ghrelin activation via acylation. Not only is GOAT abundant within stomach ghrelin cells, but emerging evidence also suggests a role of plasma GOAT in the maintenance of ghrelin activity in circulation. Other emerging evidence suggests that Aβ-induced GOAT hyperactivity may be a key factor driving ghrelin overactivation in AD-related conditions. These observations, together with the importance of ghrelin to metabolism, lead us to hypothesize that ghrelin overactivation due to GOAT hyperactivity contributes to hippocampal deficits, leading to memory loss in AD. In the proposed study, we will establish a link between GOAT hyperactivity, ghrelin overactivation, and hippocampal GHSR dysfunction (Aim1), examine the impact of GOAT/ghrelin deregulation on hippocampal metabolism (Aim2), and determine the contribution of GOAT/ghrelin deregulation to hippocampal synaptic injury and cognitive impairment in familial and sporadic AD-related conditions (Aim3). The results from this study will answer important questions about the ghrelin system in AD pathogenesis, and will suggest a novel avenue for the treatment and prevention of AD.


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 = $565,812 )
2025	2025	UNIVERSITY OF KANSAS CENTER FOR RESEARCH INC	2385 IRVING HILL RD	LAWRENCE	KS	66045	DOUGLAS	USA	Aging Research	003	7	4/7/2025	COMPETING CONTINUATION	$89
2025	2025	UNIVERSITY OF KANSAS CENTER FOR RESEARCH INC	2385 IRVING HILL RD	LAWRENCE	KS	66045	DOUGLAS	USA	Aging Research	001	7	11/22/2024	COMPETING CONTINUATION	$565,812
2025	2022	UNIVERSITY OF KANSAS CENTER FOR RESEARCH INC	2385 IRVING HILL RD	LAWRENCE	KS	66045	DOUGLAS	USA	Aging Research	000	6	11/14/2024	NON-COMPETING CONTINUATION	$0
2025	2022	UNIVERSITY OF KANSAS CENTER FOR RESEARCH INC	2385 IRVING HILL RD	LAWRENCE	KS	66045	DOUGLAS	USA	Aging Research	002	6	4/7/2025	NON-COMPETING CONTINUATION	-$89
														Subtotal = $565,812

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	UNIVERSITY OF KANSAS CENTER FOR RESEARCH INC	2385 IRVING HILL RD	LAWRENCE	KS	66045	DOUGLAS	USA	Aging Research	000	6	3/8/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $451,983 )
2022	2022	UNIVERSITY OF KANSAS CENTER FOR RESEARCH, INC.	2385 IRVING HILL RD	LAWRENCE	KS	66045	DOUGLAS	USA	Aging Research	000	6	3/31/2022	NON-COMPETING CONTINUATION	$451,983
														Subtotal = $451,983

Issue Date FY: 2021 ( Subtotal = $452,727 )
2021	2021	UNIVERSITY OF KANSAS CENTER FOR RESEARCH, INC.	2385 IRVING HILL RD	LAWRENCE	KS	66045	DOUGLAS	USA	Aging Research	002	5	4/15/2021	NON-COMPETING CONTINUATION	$452,727
2021	2020	UNIVERSITY OF TEXAS AT DALLAS	800 W CAMPBELL RD	RICHARDSON	TX	75080	DALLAS	USA	Aging Research	000	3	1/22/2021	NON-COMPETING CONTINUATION	-$451,827
2021	2020	UNIVERSITY OF KANSAS CENTER FOR RESEARCH, INC.	2385 IRVING HILL RD	LAWRENCE	KS	66045	DOUGLAS	USA	Aging Research	006	4	6/16/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$451,827
2021	2020	UNIVERSITY OF KANSAS CENTER FOR RESEARCH, INC.	2385 IRVING HILL RD	LAWRENCE	KS	66045	DOUGLAS	USA	Aging Research	004	4	4/23/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$8,237
2021	2020	UNIVERSITY OF KANSAS CENTER FOR RESEARCH, INC.	2385 IRVING HILL RD	LAWRENCE	KS	66045	DOUGLAS	USA	Aging Research	005	4	6/15/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$451,827
2021	2020	UNIVERSITY OF KANSAS CENTER FOR RESEARCH, INC.	2385 IRVING HILL RD	LAWRENCE	KS	66045	DOUGLAS	USA	Aging Research	001	4	1/25/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$451,827
2021	2020	UNIVERSITY OF TEXAS AT DALLAS	800 W CAMPBELL RD	RICHARDSON	TX	75080	DALLAS	USA	Aging Research	003	3	4/23/2021	NON-COMPETING CONTINUATION	-$8,237
														Subtotal = $452,727

Issue Date FY: 2020 ( Subtotal = $462,920 )
2020	2020	UNIVERSITY OF TEXAS AT DALLAS	800 W CAMPBELL RD	RICHARDSON	TX	75080	DALLAS	USA	Aging Research	000	3	5/13/2020	NON-COMPETING CONTINUATION	$462,920
														Subtotal = $462,920

Issue Date FY: 2019 ( Subtotal = $462,920 )
2019	2019	UNIVERSITY OF TEXAS AT DALLAS	800 W CAMPBELL RD	RICHARDSON	TX	75080	DALLAS	USA	Aging Research	000	2	4/18/2019	NON-COMPETING CONTINUATION	$462,920
														Subtotal = $462,920

Issue Date FY: 2018 ( Subtotal = $462,920 )
2018	2018	UNIVERSITY OF TEXAS AT DALLAS	800 W CAMPBELL RD	RICHARDSON	TX	75080	DALLAS	USA	Aging Research	000	1	8/13/2018	NEW	$462,920
														Subtotal = $462,920

Grand Total All Awards = $2,859,282

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GOAT-mediated ghrelin deregulation and hippocampal pathology in Alzheimer's Disease

Award Number: R01AG059753

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/15/2018

PERIOD OF PERFORMANCE END DATE: 11/30/2029

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