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Extracellular vesicle cargo and risk of NAFLD and NASH in U.S. youth

Award Number: R01DK127015
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/15/2022
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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Extracellular vesicle cargo and risk of NAFLD and NASH in U.S. youth - The prevalence of pediatric metabolic dysfunction-associated steatotic liver disease (MASLD) is escalating in US youth. MASLD in children is associated with poor long-term outcomes, including diabetes, cardiovascular disease, and higher liver-related morbidity and mortality in adulthood. Despite the clinical significance of pediatric MASLD, the mechanisms underlying its pathogenesis are poorly understood. This lack of knowledge is a major obstacle to the development of effective treatment and prevention strategies. Emerging studies support a role for extracellular vesicles (EVs) in MASLD. Circulating EVs can influence intracellular signaling, tissue injury and repair, and matrix remodeling in liver cells. Plasma EV levels discriminate between adult patients with MASLD and metabolic dysfunction-associated steatohepatitis (MASH) and are positively correlated with histological grade. We conducted a series of proof-of-principle studies that demonstrate: 1) distinctive protein signatures in plasma EVs isolated from children with MASLD, 2) MASLD-specific signatures approximate non-MASLD signatures following lifestyle intervention that reduced liver fat, and 3) isolation of hepatocyte-specific EVs showed enrichment of liver-specific proteins in MASLD. To date, however, investigations of EVs in pediatric MASLD are scarce, and the role of EV-derived cargo in MASLD pathogenesis in youth remains unknown. Here we propose a strategy to characterize the biological role of EVs in pediatric MASLD. In Aim 1, we will apply unbiased methods to study proteins and RNAs carried in circulating and hepatocyte-enriched EVs to derive characteristic signatures associated with MASLD and MASH in youth. In Aim 2, we will measure EV concentration and content in youth with MASLD who experienced changes in hepatic fat fraction following two distinct intervention modalities (i.e., intensive lifestyle and bariatric surgery). Importantly in Aim 3, we propose a series of molecular experiments to obtain mechanistic insight into the functional aspects of EV cargo. The combination of these approaches is innovative; and the strategy comprises a novel and sequentially appropriate set of aims that has not previously been used to address potential mechanisms of pathogenesis in pediatric MASLD. The focus on children is especially impactful due to the growing prevalence of MASLD in this population, the association of pediatric MASLD with poor health outcomes in adulthood, and the expected future economic burden to care for these individuals. The identification of EV-derived cargo associated with pediatric MASLD will enhance our understanding of the biological mechanisms contributing to disease pathogenesis, provide a means to improve diagnostic and therapeutic strategies, and identify new targets for potential drug development.


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 = $766,552 )
2025	2025	TRANSLATIONAL GENOMICS RESEARCH INSTITUTE	445 N 5TH ST	PHOENIX	AZ	85004	MARICOPA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	7/24/2025	NON-COMPETING CONTINUATION	$766,552
														Subtotal = $766,552

Issue Date FY: 2024 ( Subtotal = $751,351 )
2024	2024	TRANSLATIONAL GENOMICS RESEARCH INSTITUTE	445 N 5TH ST	PHOENIX	AZ	85004	MARICOPA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	2/16/2024	NON-COMPETING CONTINUATION	$704,393
2024	2024	TRANSLATIONAL GENOMICS RESEARCH INSTITUTE	445 N 5TH ST	PHOENIX	AZ	85004	MARICOPA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	5/20/2024	NON-COMPETING CONTINUATION	$46,958
														Subtotal = $751,351

Issue Date FY: 2023 ( Subtotal = $783,329 )
2023	2023	TRANSLATIONAL GENOMICS RESEARCH INSTITUTE	445 N 5TH ST	PHOENIX	AZ	85004	MARICOPA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/8/2023	NON-COMPETING CONTINUATION	$783,329
														Subtotal = $783,329

Issue Date FY: 2022 ( Subtotal = $852,047 )
2022	2022	TRANSLATIONAL GENOMICS RESEARCH INSTITUTE, THE	445 N 5TH ST STE 600	PHOENIX	AZ	85004	MARICOPA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	4/12/2022	NEW	$852,047
														Subtotal = $852,047

Grand Total All Awards = $3,153,279

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Extracellular vesicle cargo and risk of NAFLD and NASH in U.S. youth

Award Number: R01DK127015

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/15/2022

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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