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The Impact of Maternal Western Style Diet on Immune Cell Function and Development of Non-Alcoholic Fatty Liver Disease

Award Number: F30DK122672
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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Abstract/Project Summary Non-alcoholic fatty liver disease (NAFLD) is now the most common chronic liver disease worldwide. However, its pathophysiology is unresolved and treatment options are lacking. Poor maternal diet and obesity promote NAFLD in offspring, but the mechanisms by which this occurs are not clear. We propose to identify the impact of maternal western style diet (WSD) on offspring immune cell and liver phenotypes in a non-human primate (NHP) model with features similar to human pediatric NAFLD. While the pathophysiology of NAFLD is multifactorial, pro-inflammatory macrophage (Mf) activation and recruitment of bone marrow monocytes to the liver are critical for its progression. The innate immune system is derived from hematopoietic stem cells (HSCs), which reside primarily in the bone marrow. Maternal diet has been shown to skew HSC function, which may manifest as alterations in Mf development and activity, potentially promoting NAFLD progression. We find that maternal WSD in our NHP model increases fetal steatosis (liver fat), decreases proliferation of bone marrow cells and causes a proportional increase in myeloid (innate immune) cell production. Strikingly, these phenotypes are also present in juvenile NHP exposed to maternal WSD then weaned onto a healthy diet for the remainder of life. In addition, we observe dysregulated Mf cytokine response in NHP fetuses exposed to maternal WSD. Finally, hypoxia-inducible factor (HIF)-1a has emerged as a critical driver of the Mf pro-inflammatory phenotype. Our preliminary data in mice show that mice fed a WSD have increased hepatic Mf HIF1A RNA expression and HIF-1a protein stabilization has been shown to promote Mf inflammation and fibrosis in mice. This suggests that inhibiting HIF1a in bone marrow may prevent inflammatory Mf activity in NAFLD. Therefore, current data supports the novel hypothesis that maternal WSD differentially programs HSCs in utero to promote persistent myeloid cell skewing and downstream Mf dysfunction that ultimately drives liver damage and fibrosis later in life, and that Hif1a is necessary for this Mf dysfunction. To investigate this hypothesis we propose to: 1) We will utilize qPCR and microscopic techniques in livers from fetal and juvenile NHPs to determine the impact of maternal WSD on fibrosis, tissue inflammation and lipid content. We will also investigate the transcriptional phenotypes and proportions of recruited vs. resident Mf in livers, to determine the relative contributions of these cells in promoting NAFLD. 2) Identify how maternal WSD alters transcriptional pathways in HSCs responsible for shifts in HSC development, proliferation, and Mf phenotypes in NHP offspring, including Mf cytokine response. 3) We will test whether deletion of Hif1a in hematopoietic cells in mice is necessary for maternal WSD induced alterations in pro-inflammatory hepatic Mf response and fibrosis. These studies will give descriptive and mechanistic insight into how maternal WSD impacts offspring NAFLD, which may lead to new therapeutic approaches to hinder NAFLD progression or attenuate the impact of this prevalent disease.


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: 2022 ( Subtotal = $51,752 )
2022	2022	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	7/28/2022	NON-COMPETING CONTINUATION	$51,752
														Subtotal = $51,752

Issue Date FY: 2021 ( Subtotal = $32,973 )
2021	2021	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	8/4/2021	NON-COMPETING CONTINUATION	$32,973
														Subtotal = $32,973

Issue Date FY: 2020 ( Subtotal = $32,457 )
2020	2020	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	8/20/2020	NON-COMPETING CONTINUATION	$32,457
														Subtotal = $32,457

Issue Date FY: 2019 ( Subtotal = $31,953 )
2019	2019	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	9/13/2019	NEW	$0
2019	2019	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/13/2019	NEW	$31,953
														Subtotal = $31,953

Grand Total All Awards = $149,135

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The Impact of Maternal Western Style Diet on Immune Cell Function and Development of Non-Alcoholic Fatty Liver Disease

Award Number: F30DK122672

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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