Topic (AA-101) Medication Development for Hepatic Fibrosis will be addressed with our project entitled """"""""C/EBP? Peptides for the Treatment of Hepatic Fibrosis"""""""".
The Specific Aims of this proposal are: A) Synthesis of peptides related to Ac-KAVD-CHO with improved stability, cell penetration and bioavailability. These peptides were designed to yield an effective medication for human hepatic fibrosis. B) Screening of peptides with an apoptosis assay in cultured primary activated human hepatic stellate cells. Peptides inducing apoptosis of the target cell will be selected. C) Screening of peptides with caspase 8 activation assays in cultured primary activated human hepatic stellate cells, and cell-free systems. D) Screening of peptides with an acute liver injury/fibrogenesis assay in mouse models. E) Screening of peptides with toxicological [genomic;proteomic;and metabolomic] assays in highly differentiated primary human hepatocytes. F) Screening of peptides with a chronic liver fibrosis assay in mouse models [with ongoing injury]. Screening of peptides with a ribosomal S-6 kinase assay in cell-free systems. G) Screening of peptides with a multi-kinase assay in cell-free systems. There is compelling evidence that the proposed research will result in a medication for hepatic fibrosis that is at least as effective and safe as the lead peptide but with improved bioavailability, stability and/or cell penetration. Upon completion of this proposal, the selected compound will be ready for a RAID proposal to complete FDA phase 1 studies. Subsequently, a STTR proposal will be submitted to perform FDA phase 2 clinical studies in patients with chronic liver diseases in approximately 3 years. In agreement with the aims of the Recovery Act, retaining research personnel in our research group (N=3), at the Veterinarian Medical Unit (N=2;through per diem), and at the Veterans Medical Research Foundation (N=2;through indirect costs) will have a positive impact in the financial situation of these 7 individuals and their families. Moreover, the successful completion of this proposal will lead to the creation of a Small Business (under the umbrella of the University of California, San Diego), with the additional impact in the US economy Chronic liver diseases, through inflammation and injury induce the development of scar tissue in the liver;this is called liver fibrosis.

Public Health Relevance

Excessive liver fibrosis can result in liver cirrhosis, which accounts for the significant complications and mortality among the population with chronic liver diseases. The medical and financial burden of cirrhosis to the USA is substantial, as it is associated with Hepatitis B and C, fatty liver of obesity and diabetes and alcoholism. Additional knowledge gained by this work will facilitate the development of medication for the treatment of liver fibrosis. Development of effective treatments for liver fibrosis may also facilitate future treatments for lung and kidney fibrosis.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
NIH Challenge Grants and Partnerships Program (RC1)
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Special Emphasis Panel (ZRG1-DKUS-A (58))
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Doo, Edward
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Veterans Medical Research Fdn/San Diego
San Diego
United States
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Buck, Martina; Solis-Herruzo, Jose; Chojkier, Mario (2016) C/EBP?-Thr217 Phosphorylation Stimulates Macrophage Inflammasome Activation and Liver Injury. Sci Rep 6:24268
Buck, Martina; Garcia-Tsao, Guadalupe; Groszmann, Roberto J et al. (2014) Novel inflammatory biomarkers of portal pressure in compensated cirrhosis patients. Hepatology 59:1052-9
Chojkier, Mario; Elkhayat, Hisham; Sabry, Dina et al. (2012) Pioglitazone decreases hepatitis C viral load in overweight, treatment naïve, genotype 4 infected-patients: a pilot study. PLoS One 7:e31516
Buck, Martina; Chojkier, Mario (2011) C/EBP?-Thr217 phosphorylation signaling contributes to the development of lung injury and fibrosis in mice. PLoS One 6:e25497