Thursday, November 21, 2024 11/21/2024

Maternal Obesity and Pediatric NAFLD: Fetal Origins and Long-term outcomes in Non Human Primates

Award Number: R01DK128416
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY The prevalence of maternal overweight and obesity continues to increase in the U.S. and spans the spectrum of age, race and ethnicity, and socioeconomic status. Alarmingly, 1 in 10 infants and toddlers are obese, and 1 in 5 youth are both obese and at-risk for pediatric Non-alcoholic fatty liver disease (NAFLD). NAFLD can begin in utero with longitudinal studies showing an increased risk of NAFLD in adolescents born to obese mothers. Some features of NAFLD are similar in children and adults, yet portal fibrosis and inflammation are more common in pediatric NASH patients than adult patients, and portends a rapid progression to end-stage liver disease in early adulthood for reasons that remain poorly understood. Our group has spent the past decade developing and characterizing a sophisticated nonhuman primate (NHP) model of high fat/calorically dense maternal diet consumption that has critically important developmental and physiological similarities to humans. Data from our well-characterized NHP model demonstrate that maternal Western-style diet (MWSD) triggers fetal hepatic collagen deposition in the portal triad and stellate cell activation that persists in 3-year-old (3YO) juvenile animals, despite switching to a healthy chow diet at weaning. Notably, 2 miRNAs with critical roles in liver metabolism and inflammatory responses were significantly increased (miR-122) or decreased (miR-34a) in fetal liver and partially normalized when obese mothers were switched to a healthy chow diet. Our results suggest these miRNAs are diet-sensitive and candidate targets for epigenetic priming of NAFLD early in life. Our preliminary data in 3YO NHP offspring also show that MWSD reprograms hematopoietic stem cell progenitors (HSPC)s and bone marrow derived macrophages (BMDM) to a glycolytic phenotype and a blunted response to IL-4, suggesting decreased anti-inflammatory capacity and impaired Mφ ability to assume a reparative phenotype. Given the importance of M2-like Mφ for healing liver injury,our overall hypothesis is that MWSD alters miRNAs in liver in parallel with epigenetically reprogrammed HSPC and liver Mφ before birth. This leads to ongoing production of hyper-inflammatory Mφ and the inability to resolve liver injury across the lifespan. The overarching goal of this proposal is to understand the mechanistic basis by which MWSD drives epigenetic remodeling and the pathogenesis for NAFLD beginning in utero. In this revised application, our Aims are to: 1) Test the hypothesis that MWSD alters binding of fetal miR-34a, and miR-122 to specific targets in fetal liver, and identify macrophage sub-sets in Juvenile livers using single cell RNAseq; 2) Test the hypothesis that MWSD drives pro-inflammatory functions in isolated fetal and 3YO HSPC and liver Mφ through distinct transcriptional and epigenetic mechanisms. 3) Test the hypothesis that MWSD disrupts BA signaling and HNF4α in MWSD hepatocytes and preferentially affects periportal hepatocytes in fetal and post-natal livers.Taken together, using fetal and Juvenile NHP, which have developmental features similar to humans, we will decipher how MWSD exposure triggers epigenetic and inflammatory modifications in HSPC and liver Mφ that drive novel pathways underlying pediatric NAFLD.


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: 2024 ( Subtotal = $536,924 )
2024	2024	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	7/18/2024	NON-COMPETING CONTINUATION	$536,924
														Subtotal = $536,924

Issue Date FY: 2023 ( Subtotal = $572,644 )
2023	2023	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	6/26/2023	NON-COMPETING CONTINUATION	$572,644
														Subtotal = $572,644

Issue Date FY: 2022 ( Subtotal = $582,919 )
2022	2022	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	6/15/2022	NON-COMPETING CONTINUATION	$582,919
														Subtotal = $582,919

Issue Date FY: 2021 ( Subtotal = $602,100 )
2021	2021	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/22/2021	NEW	$602,100
														Subtotal = $602,100

Grand Total All Awards = $2,294,587

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Maternal Obesity and Pediatric NAFLD: Fetal Origins and Long-term outcomes in Non Human Primates

Award Number: R01DK128416

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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