THE ROLE OF UNACYLATED GHRELIN ON AGE-ASSOCIATED PROGRESSIVE MUSCLE WEAKNESS AND CACHEXIA ELICITED BY CANCE…

Assistance award details

Assistance award identifier

ASST_NON_R00AG064143_075

FAIN

R00AG064143

Recipient

WAKE FOREST UNIVERSITY HEALTH SCIENCES

Awarding agency

Department of Health and Human Services

Funding agency

Department of Health and Human Services

Assistance listing (CFDA)

93.866

Total obligated

$842,972

Period

Feb 15, 2020 – Jan 31, 2025

Fiscal year

2022

Place of performance state

NC

Source file

FY2022_All_Assistance_Full_20261006.zip

Description

THE ROLE OF UNACYLATED GHRELIN ON AGE-ASSOCIATED PROGRESSIVE MUSCLE WEAKNESS AND CACHEXIA ELICITED BY CANCER - PROJECT SUMMARY/ABSTRACT SKELETAL MUSCLE WEAKNESS IS A HALLMARK OF AGING AND CANCER CACHEXIA THAT SIGNIFICANTLY AFFECT INDIVIDUAL HEALTHSPANS AND QUALITY OF LIFE. DESPITE THE CLINICAL SIGNIFICANCE, NO PHARMACOLOGICAL THERAPIES ARE CURRENTLY AVAILABLE TO MITIGATE MUSCLE ATROPHY AND WEAKNESS. 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 (AG) BINDS TO ITS RECEPTOR IN THE BRAIN, GROWTH HORMONE SECRETAGOGUE RECEPTOR-1A (GHSR1A). AN ACUTE RISE IN AG 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 FORM OF GHRELIN (UNAG) ON MUSCLE, INDEPENDENT OF GHSR1A ACTIVATION. INCUBATING MYOBLAST WITH UNAG INCREASES DIFFERENTIATION AND FUSION INTO MYOTUBES, AND INHIBITED GLUCOCORTICOID-INDUCED MUSCLE ATROPHY AND PROTEOLYTIC MARKERS. DURING A 2-DAY FASTING AND 14-DAY DENERVATION, A CHRONIC INCREASE IN CIRCULATING UNAG USING A GENETIC MODIFICATION PREVENTED SKELETAL MUSCLE ATROPHY INDEPENDENT OF ACTIVATION OF THE GROWTH HORMONE/IGF-1 AXIS VIA GHSR1A. THE GOAL OF THIS PROPOSAL IS TO TEST THE ABILITY OF UNAG 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 UNAG PREVENTS NEUROGENIC ATROPHY WITH AGING BY ALTERING RATES OF PROTEIN SYNTHESIS AND DEGRADATION IN MUSCLE. AIM 2: TO DETERMINE WHETHER UNAG PREVENTS CONTRACTILE DYSFUNCTION WITH AGING THROUGH MODULATIONS OF CALCIUM HANDLING AND SENSITIVITY. AIM 3: TO DETERMINE WHETH