This application is for the Continuation of the Case Western Reserve University (CWRU) Clinical Site and its Subsites of the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN). Nonalcoholic fatty liver disease (NAFLD) affects nearly a third of adults and a fifth of children in North America and is a major public health issue in the United States. NAFLD, and especially nonalcoholic steatohepatitis (NASH), 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 burden of NASH that can only be addressed through this large research consortium with a demonstrated track record of success in previous cycles. The primary objective of the NASH CRN is to perform clinical research on NASH and NAFLD in adults and children. Another high priority 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. CWRU has played a leading role in both the clinical and translational research success of the NASH CRN since the inception. CWRU was a leading enrolling site in both the PIVENS and FLINT trials. CWRU investigators are uniquely placed in improving understanding of systemic abnormalities including cardiovascular and skeletal muscle dysfunction in NAFLD. The role of sarcopenia and myostatin, a TGF? superfamily member, as a therapeutic target in NASH is a paradigm shifting approach to novel targets for the nearly ubiquitous disease. Given the high recruitment, retention and quality of data from CWRU, and our continued commitment to the success of the collaboration, the NASH CRN is poised to continue its major impact on the field and directly advance the mission of the NIH to improve the health of the public.

Public Health Relevance

Nonalcoholic fatty liver disease (NAFLD) affects nearly a third of adults and a fifth of children in North America. The spectrum of NAFLD ranges from fatty liver to nonalcoholic steatohepatitis (NASH) and NASH cirrhosis. NAFLD, especially NASH, is associated with increased liver-, cardiovascular-, and cancer-related mortality. The goal of the NASH CRN is to transform scientific discoveries from laboratory, clinical, and epidemiological studies into clinical applications to reduce the burden of the disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
2U01DK061732-13
Application #
8774456
Study Section
Special Emphasis Panel (ZDK1-GRB-7 (M2))
Program Officer
Doo, Edward
Project Start
2002-06-15
Project End
2019-06-30
Budget Start
2014-08-01
Budget End
2015-06-30
Support Year
13
Fiscal Year
2014
Total Cost
$375,544
Indirect Cost
$145,816
Name
Cleveland Clinic Lerner
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Dasarathy, Srinivasan (2016) Cause and management of muscle wasting in chronic liver disease. Curr Opin Gastroenterol 32:159-65
Dasarathy, Srinivasan (2016) Nutrition and Alcoholic Liver Disease: Effects of Alcoholism on Nutrition, Effects of Nutrition on Alcoholic Liver Disease, and Nutritional Therapies for Alcoholic Liver Disease. Clin Liver Dis 20:535-50
Davuluri, Gangarao; Allawy, Allawy; Thapaliya, Samjhana et al. (2016) Hyperammonaemia-induced skeletal muscle mitochondrial dysfunction results in cataplerosis and oxidative stress. J Physiol 594:7341-7360
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
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
Dasarathy, Srinivasan; Merli, Manuela (2016) Sarcopenia from mechanism to diagnosis and treatment in liver disease. J Hepatol 65:1232-1244
Dasarathy, Srinivasan; Dasarathy, Jaividhya; Khiyami, Amer et al. (2016) In Response. J Clin Gastroenterol 50:181
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
Corey, Kathleen E; Vuppalanchi, Raj; Vos, Miriam et al. (2015) Improvement in liver histology is associated with reduction in dyslipidemia in children with nonalcoholic fatty liver disease. J Pediatr Gastroenterol Nutr 60:360-7
Bazick, Jessica; Donithan, Michele; Neuschwander-Tetri, Brent A et al. (2015) Clinical Model for NASH and Advanced Fibrosis in Adult Patients With Diabetes and NAFLD: Guidelines for Referral in NAFLD. Diabetes Care 38:1347-55

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