Assistant Clinical Professor
Cedars Sinai Medical Center
United States of America
As a scientist with broad-based training in the field of liver diseases, I have the necessary experience and motivation to carry out the proposed research. I have focused my research on the molecular mechanisms that promote liver fibrosis with specific emphasis on hepatic stellate cell (HSC) activation. My Ph.D. and postdoctoral experience in the field of liver research makes me suitable to work in the field of liver fibrosis. As a Ph.D. student at the University of Delhi, India, I prepared site-specific gene delivery vehicles that could target hepatocytes. During the period from 2000-2004, my academic career was disrupted due to family obligations. I came back to academia in 2005 when I re-started my work as a postdoctoral fellow at the Southern California research center for ALPD and cirrhosis of the University of Southern California (USC). I worked on the role of methionine adenosyltransferase (MAT) genes in liver carcinogenesis and their interplay with pro-fibrogenic growth factor, leptin. This novel work led me to expand this analysis to the study of HSC activation and liver fibrosis. In 2009 I received the K99/R00 award from NIH and was promoted to Assistant Professor of Medicine at USC. During this period, I unraveled novel roles of MAT genes in HSC activation and made progress towards understanding the mechanisms that control the MAT2A gene in quiescent and activated HSCs in rat models of liver injury. While investigating the regulation of MAT genes in primary human HSCs, I identified phosphorylation as a mechanism by which MAT proteins were stabilized in activated human HSCs and exhibited novel cross-talk with key proteins during transition to myofibroblastic state. I am now a faculty of the liver research group of Cedars-Sinai Medical Center. My ongoing effort to identify novel targets for liver fibrosis therapy has led me to the current proposal that is focused on examining the role of the scaffolding proteins, A-kinase anchor proteins (AKAP) in alcoholic liver disease. My preliminary work has shown that pro-fibrogenic stimuli such as ethanol and platelet-derived growth factor (PDGF) induce the phosphorylation of AKAPs and these proteins regulate proliferative and collagen activation pathways in HSCs. These functions of AKAPs in HSC activation and alcoholic liver fibrosis have not been described thus far. The current proposal aims at testing the novel hypothesis that phosphorylation of AKAPs de-regulate their scaffolding activity on key signaling proteins leading to enhanced HSC activation and liver fibrosis. The excellent academic environment at Cedars-Sinai Medical Center is ideal to pursue my goals. I have built excellent collaborations and have complete support, laboratory space and facilities from my OMB No. 0925-0001/0002 (Rev. 08/12 Approved Through 8/31/2015) Department Director, Dr. Shelly Lu. I believe that my experience in the field of HSC activation, fibrosis and my molecular biology experience in evaluating functional outcomes of post-translational modifications will help me to successfully accomplish the aims that I have put forward in the current proposal.
The research of Komal Ramani, PhD, focuses on two areas: interactions of methionine adenosyltransferases (MAT) proteins during liver injury, and evaluation of gravin as a molecular target in liver fibrosis. Ramani is evaluating how the phosphorylation of MAT proteins affects fibrogenic phenotype in the liver. Preliminary work from her laboratory has shown that MAT proteins can signal the phosphorylation of the scaffolding protein AKAP12, or gravin, in human hepatic stellate cells (HSCs). Gravin phosphorylation has been shown in other systems to promote cellular proliferation via a cyclin-D1-dependent mechanism, but how this affects liver fibrosis is unknown. Ramani also is examining the role of gravin during development of liver fibrosis. Her preliminary analysis has shown that gravin phosphorylation is enhanced during human HSC activation and that expression of gravin is intrinsically linked to cell proliferation caused by platelet-derived growth factor (PDGF). She is examining whether the gravin-PDGF axis promotes HSC mitogenesis and is a putative molecular target in liver fibrosis. The long-term goal of these projects is to identify small molecules to block the pathways of gravin or MAT phosphorylation, thereby blocking the progression of HSC activation and liver fibrogenesis.