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Pranoti Mandrekar, Ph.D.

Department of Medicine

Director, Translational Science Program
Director, NIH Summer Research Program

Graduate School of Biomedical Sciences

Other Affiliation(s):

Director, Undergraduate Medical Summer Research Program

STRESS RESPONSES AND PROTEOSTASIS REGULATORS IN LIVER INFLAMMATION ANND FIBROSIS

Research in my laboratory focuses on understanding the signaling mechanisms involved in innate immune cell activation during liver injury and cancer. The physiological function of the liver is elimination of pathogens and antigens from the blood for which mounting of an immune response is required. To avoid unnecessary activation of the immune system, the liver develops a local immune response followed by induction of peripheral tolerance towards the antigen. When stressful agents such as pathogens or environmental insults challenge the liver for extended periods of time and their elimination is not possible, inflammation and injury follows. The onset of inflammation in the liver is followed by fibrosis, cirrhosis and liver cancer. Thus, studying the mechanisms involved in liver inflammation will provide major insights into pathogenesis of liver disease and progression.

Using various in vivo and in vitro models, we are studying the role of innate immune signaling pathways, their crosstalk with oxidative stress mechanisms leading to pro-inflammatory cytokine production. We are also focusing on investigating the role of chemokine responses and their effect on recruitment of bone-marrow derived cells and immune cells in the liver during development and progression of liver disease. Recent studies initiated in our lab focus on the impact of alcohol drinking on breast and liver cancer. Th main areas of focus are:

1) Proteostasis mechanisms in fatty liver disease, inflammation and fibrosis

Characterization of an interplay of immune and oxidative stress related mechanisms involved in mediating the effects of acute and chronic alcohol consumption, and epigenetic pathways altered in chronic liver diseases using alcoholic and non-alcoholic liver disease models are being studied. We identified a pathogenic role for stress mediated transcription factor HSF1 and its target gene, hsp90 and hsp70 in innate immune cells resulting in regulation of inflammatory responses. Using molecular and targeted translational approaches we are currently evaluating hsp90 and hsp70 as a therapeutic targets in manipulation of macrophage function in host defense and liver diseases such as alcoholic liver disease and fibrosis.

Recently we are interested on the role of alcohol mediated proteostasis regulator, HSP90 on the microbiome and intestinal function. Extending these studies we hypothesize the role of the gut-braiin axis in progression of alcohol related liver disease. Currently we are assessing the impact of HSP90 inhibitors on the intestinal permeability and microbiome to understand the overall role of proteostasis on gut-brain-liver in alcoholic hepatitis.

2) Chemokines and importance of immune liver cell types in liver injury

The dynamic role of immune cells and bone marrow derived hematopoietic cells and their cross talk with other liver cell types in promoting liver diseases is being investigated. Liver macrophages, dendritic cells, NK and NKT cells play an important function in development and progression of liver disease. We propose to unravel the role of chemokinesin recruitment of immune cells in the liver and modulate chronic liver injury. Specifically, studies from our laboratory have identified a significant role for a CC-chemokine, monocyte chemoattractant protein -1 (MCP-1) in induction of fatty liver disease. We hypothesize that CCL2 is an important link between innate immune mechanisms and steatosis or fatty liver. Other chemokines and chemokine receptors are also being explored to determine the role of MCP-1 in mediating inflammatory processes leading to alcoholic liver injury.

3) Impact of binge/moderate alcohol on immune response

Acute/moderate alcohol consumption alters innate and adaptive immune function reducing host defense including antibacterial, anti-viral and tissue repair and predisposing to infections and trauma contributing to impairment of health. Studies addressing mechanisms associated with moderate alcohol induced immune suppression leading to increased susceptibility if infections and trauma are limited leaving the clinician with no therapeutics to rectify altered immune function. To date no studies have identified signaling proteins that can be potentially developed as therapeutic targets in alcohol induced immune effects. Understanding the mechanisms linked to acute/moderate alcohol induced immune suppression will thus provide insight into the molecular pathogenesis of interactions of host defense and alcohol and also extend our horizons to identify therapeutic targets to restore normal immune function. Results from our studies will also have a broader applicability to the understanding of the molecular mechanisms affected by alcohol use with relation to multiple organs including the cardiovascular system, lung and liver. More importantly, these studies will answer a biologically highly relevant question at the cellular level and help identify novel therapeutic molecular targets for restoration of normal innate immune responses.

 

 

 


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