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The role of unacylated ghrelin in age-associated progressive muscle weakness and cachexia elicited by cancer.

Award Number: R00AG064143
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/15/2020
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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The role of unacylated ghrelin in age-associated progressive muscle weakness and cachexia elicited by cancer. - Project Summary/Abstract Skeletal muscle weakness is a hallmark of aging and cancer cachexia with significant impacts on individual healthspan and quality of life. Despite the clinical significance, no pharmacological therapies are currently available to attenuate muscle atrophy and weakness in the elderly and in patients with cancer cachexia. The goal of this project is to test the ability of a novel and promising pharmacological intervention, unacylated ghrelin, to delay skeletal muscle weakness and loss of muscle mass in aging and in cancer cachexia. Ghrelin is a hormone that increases appetite when the acylated ghrelin binds to its receptor in the brain, growth hormone secretagogue receptor-1a (GHSR1a). An acute rise in acylated ghrelin increases lean mass in wasting conditions, but a concurrent increase in adiposity and decreased sensitivity in GHSR1a receptor lead to atrophy and contractile dysfunction. In contrast, recent studies show a direct beneficial effect of the unacylated ghrelin on muscle, independent of GHSR1a activation. Incubating myoblast with unacylated ghrelin increases differentiation and fusion into myotubes, and inhibited glucocorticoid-induced muscle atrophy and proteolytic markers. An increase in unacylated ghrelin protected skeletal muscle from denervation-induced atrophy. Therefore, the goal of this proposal is to test the ability of unacylated ghrelin to mitigate loss of muscle mass and weakness in two distinct degenerative conditions-sarcopenia and cancer cachexia. The following aims are proposed: Aim 1: To determine whether unacylated ghrelin prevents neurogenic atrophy with aging by altering rates of protein synthesis and degradation in muscle. Aim 2: To determine whether unacylated ghrelin prevents contractile dysfunction with aging through modulations of calcium handling and sensitivity. Aim 3: To determine whether unacylated ghrelin prevents a rapid wasting and contractile dysfunction in cancer cachexia. In order to understand the molecular mechanisms of unacylated ghrelin in skeletal muscle cells, member of my laboratory will perform state-of-the art molecular biology and integrative physiology techniques to assess in vivo protein turnover rate and calcium handling and sensitivity of myofilaments. If the results support our hypothesis, clinical trials will be warranted. Unacylated ghrelin and its synthetic peptides have excellent safety profiles in humans and animals with null association to cancer cell growth.


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	2024	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Aging Research	001	5	1/16/2026	SUPPLEMENT FOR EXPANSION	$0
2026	2024	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Aging Research	000	5	1/16/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $341,466 )
2024	2024	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Aging Research	001	5	4/4/2024	SUPPLEMENT FOR EXPANSION	$92,466
2024	2024	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Aging Research	000	5	1/29/2024	NON-COMPETING CONTINUATION	$224,101
2024	2024	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Aging Research	002	5	6/14/2024	NON-COMPETING CONTINUATION	$24,899
														Subtotal = $341,466

Issue Date FY: 2023 ( Subtotal = $249,000 )
2023	2023	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Aging Research	000	4	2/17/2023	NON-COMPETING CONTINUATION	$249,000
														Subtotal = $249,000

Issue Date FY: 2022 ( Subtotal = $252,506 )
2022	2022	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Aging Research	002	3	6/3/2022	EXTENSION WITH OR WITHOUT FUNDS	$3,506
2022	2022	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Aging Research	000	3	4/14/2022	EXTENSION WITH OR WITHOUT FUNDS	$249,000
2022	2022	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Aging Research	001	3	4/27/2022	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $252,506

Grand Total All Awards = $842,972

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The role of unacylated ghrelin in age-associated progressive muscle weakness and cachexia elicited by cancer.

Award Number: R00AG064143

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/15/2020

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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