Researchers uncover novel candidate drug targets for nonalcoholic fatty liver disease (NAFLD) by using the latest techniques, including single-nuclear sequencing of mice and human liver tissue, and to characterize key scar-producing liver cells Includes advanced 3D glasses imaging of mice. , The research was led by investigators from the Icahn School of Medicine at Mount Sinai. Using these innovative methods, the investigators discovered a network of cell-to-cell communication driving the progression of liver disease. The findings, published in Science Translational Medicine, could lead to new treatments.
Characterized by fat in the liver and often associated with type 2 diabetes, hypertension and increased blood lipids, NAFLD is a worldwide threat. In the United States, 30 to 40 percent of adults are estimated to be affected, with about 20 percent of these patients having a more advanced stage called non-alcoholic steatohepatitis, or NASH, which is marked by inflammation of the liver and can progress to chronic liver disease. Could Advanced scarring (cirrhosis) and liver failure. NASH is also the fastest growing cause of liver cancer worldwide. Because advanced stages of NASH are characterized by accumulation of fibrosis or scarring, efforts to prevent fibrosis are at the heart of efforts to treat NASH, yet there is no drug approved for this purpose, the investigators say.
As part of the experiments, the researchers performed single-nuclear sequencing in a mouse model of NASH and in a parallel study human liver tissue from nine subjects with NASH and two controls. They identified 68 shared pairs of potential drug targets in the two species. In addition, the investigators followed up one of these pairings by testing an existing cancer drug in mice as a proof of concept. stellate cells, which are the major scar-causing cells in the liver,” said senior study author Scott L. Friedman, MD, Irene and Dr. Mount Sinai. “In combination with this new glass liver imaging approach — an advanced tissue clearing Method that Enables Deeper Insight – With gene expression analysis in individual stellate cells, we have unveiled an entirely new understanding of how these cells generate scars such as NASH. progresses in the late stages.”
The researchers found that in advanced disease, stellate cells develop a dense network of interactions that facilitate these 68 unique interaction pairs, which were not previously identified in this disease. First author Shuang (Sammi) said, “We confirmed the importance of such a pair of NTF3-NTRK3 proteins using a molecule previously developed to block NTRK3 in human cancer and developed a new drug to fight NASH fibrosis.” re-formulated it to establish its potential as a medicine.” ) Wang, PhD, an instructor in the Department of Liver Diseases. “This new understanding of fibrosis development suggests that advanced fibrosis may have a unique repertoire of signals that accelerate scarring, representing a previously unrecognized set of drug targets.”
The researchers hypothesize that the circuitry of how cells communicate with each other evolves as the disease progresses, so some drugs may be more effective earlier and others at more advanced stages. And a single drug may not work for all stages of the disease. The investigators are currently working with Icahn Mount Sinai chemists to further optimize NTRK3 inhibitors for the treatment of liver fibrosis. Next, the investigators plan to functionally screen all candidate interactors in a cell-culture system, followed by testing in preclinical models of liver disease, as they have done for NTRK3. In addition, they hope to expand their efforts to determine whether similar interactions between fibrogenic cells underlie fibrosis of other tissues, including the heart, lung and kidney. The paper is titled “An autocrine signaling circuit in hepatic stellate cells underlying advanced fibrosis in non-alcoholic steatohepatitis.”
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