Debanjali Dasgupta Awarded ALF Research Award for Important Work on NASH
Alexander M. White, III Memorial Postdoctoral Research Fellowship Award
Debanjali Dasgupta, PhD
Hepatic IRE1alpha activation induces EV release, leading to hepatic injury
Mentor: Harmeet Malhi, MBBS
What is your first memory/experience of wanting to be involved in scientific research?
At the age of fifteen, I was asked by my high school teacher about my future plan. I did not have any good answer. I just told her that I want to work on bioscience. I want to explore new things in this field. She told me “Oh, you want to be a scientist then.” That sentence stuck in my mind.
How did you learn that you had won an ALF Research Award?
I got an email from Savonne Johnson, Consultant, Research Awards, ALF on June 24 at 7:39am. This email made my day.
Describe your Research Award Project in very simple (layman) language?
Extracellular vesicles (EVs) are cell derived membrane surrounded structures released both basally and under stress conditions. Depending on the microenvironment and the disease status, secretion rate and content in EVs varies; which are implicated in disease pathophysiology. Inositol requiring enzyme-1 alpha (IRE1α), an ER stress sensor molecule, is activated in numerous sterile inflammatory liver diseases including nonalcoholic steatohepatitis (NASH). The proposed study is aimed to interrogate the contribution of IRE1α-mediated pathway in the regulation of liver-derived EV release and its role in promoting liver injury. To test this hypothesis we will employ a gain-of-function approach to activate IRE1α and loss-of-function approach using a pharmacologic inhibitor, 4μ8C, to inhibit IRE1α. Hepatic injury and inflammation will be screened in mice model of both approaches. EVs will be isolated from plasma of treated mice and will further be screened for its content. We anticipate that IRE1α is sufficient to stimulate the release of EVs from liver leading to hepatic injury and inflammation which is ameliorated in presence of 4μ8C. As the EV release and the pathogenic role of IRE1α are ameliorated in presence of 4μ8C, it may act as a potential therapeutic strategy in liver diseases.
What do you hope your research project will lead to:
- In the short term?
My research project will enlighten the contribution of ER stress in liver disease, especially in nonalcoholic steatohepatitis (NASH).
- In its overall contribution to a specific area of liver research?
NASH, which affects 5% of the population of the United States of America (approximately 16 million individuals), is a significant public health problem, the leading cause of chronic liver disease in this country, and predicted to be the dominant indication for liver transplantation in the near future. There are no regulatory agency-approved therapies for NASH. Recruited macrophage comprised innate immune-mediated inflammation is a key determinant of disease progression in NASH. Steatotic stressed hepatocytes release EVs, which can influence macrophage responses in vitro, specifically induce macrophage chemotaxis towards lipototoxic EVs. The contribution of this research proposal is to answer the novel question: Is the ER stress sensor IRE1α sufficient to induce the release of proinflammatory EVs to promote liver injury? This actionable information would not only explain how the ER stress sensor IRE1α induces hepatic injury and inflammation, but would also lead to potential new therapeutic strategies for human NASH, such as with the novel small molecule IRE1α inhibitors, such as 4μ8C or MKC-3946.
How did you first hear about the ALF Research Award Program?
My mentor told me.
What is the one thing you would like readers to know about why liver research is so important?
Liver is the primary organ for metabolism of food. It provides the body with the necessary nutrients and maintains the body homeostasis. Besides it serves as the filtration system for converting toxins to waste products. Now days, liver disease is one of the major health concern worldwide due to the stress, poor work-life balance and food habit. As a fundamental part of the body’s regulation, it’s paramount to keep the liver healthy for getting a healthy life style.
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