This application is for the Continuation of the Virginia Mason Medical Center (VMMC) Clinical Site and its Subsites of the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN). Nonalcoholic fatty liver disease (NAFLD) affects one out of every three adults and five children in North America and is a growing public health issue in the United States. NAFLD, and especially nonalcoholic steatohepatitis (NASH), may lead to end-stage liver disease and primary liver cancer, as well as liver-, cardiovascular-, and cancer-related mortality, resulting in major increases in health burdens and costs. The NASH CRN is ideally and uniquely positioned to impact the growing public health significance of NASH that can only be addressed via a large research consortium. The primary objective of the NASH CRN is to perform clinical research on NASH and NAFLD in adults and children. A closely linked and high priority secondary objective is to conduct translational research in NASH and NAFLD focusing on the pathogenesis that will provide the basis for understanding the natural history and developing means of better diagnosis, treatment, and clinical management. In the next phase of the NASH CRN, the adult and pediatric therapeutic trials initiated during the previous funding cycle will be completed, and new therapeutic trials, including phase 2a proof of mechanism and phase 2b clinical trials will be initiated, to develop evidence-based treatment options that are safe, effective, simple, and inexpensive. The longitudinal cohort of adults and children with NAFLD will be extended, which will prospectively define the natural history of the disease, the cardiovascular and metabolic risk factors, and will aid in biomarker discovery and validation, and development and validation of non-invasive techniques to evaluate and identify those with NASH/NAFLD, who will respond, and how quickly the disease is progressing. VMMC has played a leading role in both the clinical and translational research success of the NASH CRN since the inception. VMMC was a leading enrolling site in both the PIVENS and FLINT trials. VMMC currently has 5 ongoing NASH CRN approved ancillary studies, including AS40, "The Role of Iron Pathogenesis of NAFLD" (R01DK087696), which has made major contributions toward understanding the effect of iron in NAFLD. VMMC investigators have contributed 20 presentations at national and international scientific meetings and coauthored 14 manuscripts on behalf of the NASH CRN. The NASH CRN is poised to continue its major impact on the field and directly advance the mission of the National Institutes of Health to improve the health of the public.

Public Health Relevance

Nonalcoholic fatty liver disease (NAFLD) affects one in three adults and one in five children in North America. NAFLD ranges from nonalcoholic fatty liver to nonalcoholic steatohepatitis (NASH). NAFLD, especially NASH, is associated with increased liver-, cardiovascular-, and cancer-related mortality. The NASH CRN aims to transform scientific discoveries from laboratory, clinical, and population studies into clinical applications to reduce the incidence and burden of adverse outcomes due to NAFLD and NASH.

Agency
National Institute of Health (NIH)
Type
Research Project--Cooperative Agreements (U01)
Project #
2U01DK061728-14
Application #
8771232
Study Section
Special Emphasis Panel (ZDK1)
Program Officer
Doo, Edward
Project Start
Project End
Budget Start
Budget End
Support Year
14
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Benaroya Research Institute at Virginia Mason
Department
Type
DUNS #
City
Seattle
State
WA
Country
United States
Zip Code
98101
Klair, Jagpal Singh; Yang, Ju Dong; Abdelmalek, Manal F et al. (2016) A longer duration of estrogen deficiency increases fibrosis risk among postmenopausal women with nonalcoholic fatty liver disease. Hepatology 64:85-91
Nelson, J E; Handa, P; Aouizerat, B et al. (2016) Increased parenchymal damage and steatohepatitis in Caucasian non-alcoholic fatty liver disease patients with common IL1B and IL6 polymorphisms. Aliment Pharmacol Ther 44:1253-1264
Yeh, Matthew M; Belt, Patricia; Brunt, Elizabeth M et al. (2016) Acidophil bodies in nonalcoholic steatohepatitis. Hum Pathol 52:28-37
Schwimmer, Jeffrey B; Lavine, Joel E; Wilson, Laura A et al. (2016) In Children With Nonalcoholic Fatty Liver Disease, Cysteamine Bitartrate Delayed Release Improves Liver Enzymes but Does Not Reduce Disease Activity Scores. Gastroenterology 151:1141-1154.e9
Abdou, Reham M; Zhu, Lixin; Baker, Robert D et al. (2016) Gut Microbiota of Nonalcoholic Fatty Liver Disease. Dig Dis Sci 61:1268-81
Kanwar, Pushpjeet; Nelson, James E; Yates, Katherine et al. (2016) Association between metabolic syndrome and liver histology among NAFLD patients without diabetes. BMJ Open Gastroenterol 3:e000114
Zhu, Lixin; Baker, Robert D; Baker, Susan S (2015) Gut microbiome and nonalcoholic fatty liver diseases. Pediatr Res 77:245-51
Aljomah, Ghanim; Baker, Susan S; Liu, Wensheng et al. (2015) Induction of CYP2E1 in non-alcoholic fatty liver diseases. Exp Mol Pathol 99:677-81
Corey, K E; Vuppalanchi, R; Wilson, L A et al. (2015) NASH resolution is associated with improvements in HDL and triglyceride levels but not improvement in LDL or non-HDL-C levels. Aliment Pharmacol Ther 41:301-9
Neuschwander-Tetri, Brent A; Loomba, Rohit; Sanyal, Arun J et al. (2015) Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 385:956-65

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