Would you tell us what sparked your interest in science?
I think I just developed an interest in science over time. My undergraduate course in microbiology and a graduate course in clinical biochemistry boosted me even more to be involved in researching basic, fundamental questions about human diseases.
What got you interested in studying liver inflammatory disorder, primary sclerosing cholangitis (PSC)?
During my postdoctoral fellowship, I examined the mechanism of liver injury in an autophagy-deficient liver using Atg7 or Atg5 genetic knockout rodent models. Autophagy deficiency in the liver causes hepatic inflammation, fibrosis, and tumorigenesis via an unknown mechanism. How hepatic injury causes liver inflammation and other liver pathologies, is one of the fascinating questions for us and many scientists in the field. PSC is also pathologically characterized by hepatic inflammation (cholangitis), biliary scarring (fibrosis), the mechanism being unknown. I found PSC very interesting and being a rare disease, very few scientists study it. Also, I wanted to gear my research direction into more human disease models.
The pathology of PSC is poorly understood and, currently, the only treatment for PSC is a liver transplant. Tell me more about how your research aims to address or understand these big picture issues.
The major roadblock for treatment of PSC is the lack of detailed understanding of how inflammatory response targeting biliary epithelial cells are triggered. Our study examines the mechanism by identifying the hepatic factors or cellular processes and understanding hepatic inflammation in PSC. Hence our study not only generates new pathogenesis-related information but also helps develop therapeutic targets for PSC treatment down the road.
Your BeHEARD proposal focuses on PSC and the potential role autophagy defects and proteostasis dysregulation plays is disease progression and pathology. Can you share what led you to these hypotheses about the involvement of Rab GTPases and impaired HSF-1 function, respectively?
The underlying pathogenic mechanism of PSC is largely unknown. One such pathogenic driver that we identified in the preclinical model of PSC is disturbance in hepatic proteostasis due to defects in autophagic vesicular trafficking. Autophagy vesicular trafficking is impaired at the level of autophagosomes and lysosomal fusion resulting in protein inclusion formation. Moreover, abnormal protein inclusion formation is mechanistically linked to the downregulation of heat shock factor 1 (HSF-1) transcription factor, a master regulator of proteotoxic stress. Both of these cellular events occur in the epithelial cellular compartment including biliary cells. These findings implicitly suggest that impaired autophagy vesicular fusion and deregulated proteostasis pathway could be the potential pathogenic mechanism for PSC development. Thus, our overall hypothesis here is that impairment of autophagosome-lysosomal fusion together with deregulated proteostasis regulators is an important molecular mechanism that could drive the pathogenesis of PSC. We believe, these intracellular events are linked to secretion of pathogenic protein factors to elicit an inflammatory response in PSC. Thus, the project will explore a novel and previously uncharacterized mechanism that contributes to the development and progression of PSC. Also, understanding the role of hepatic proteostasis factors will be instrumental in clinical prevention and management of PSC.
Tell me about what exciting research projects are happening in your lab.
Broadly, my lab is currently working on two major research themes-
- To examine the role of autophagy in hepatic metabolism: We are examining how hepatic autophagy contributes to metabolic homeostasis via regulating various signaling proteins such as FXR and nuclear receptors.
- To determine the mechanism of liver disease, degeneration, and regeneration (DDR) using various models (genetic, dietary, hepatotoxin etc.) of liver injury. We are specifically identifying various hepatic factors and their role in the causation of liver inflammation, fibrosis, and tumorigenesis.
It seems your PSC research bridges the topics of inflammation and autophagy. What developments in these fields are most exciting to you?
Recent literature suggests that autophagy, which is conventionally known to execute intracellular degradation, plays a novel role in the secretion of hepatic factors via exosomes or specific vesicles (senescence-associated secretory phenotypes). The release of various autophagy-mediated hepatic factors and their pathogenesis role in biliary inflammation is an exciting area of research that may open a new therapeutic avenue for the treatment of PSC.
Describe why your research is important to the ordinary citizen.
We do fundamental research in understanding the mechanism of liver injury, inflammation, fibrosis, and tumorigenesis, which are common pathologies observed in many human liver diseases. Our published and ongoing research suggests the involvement of different hepatic factors and cellular processes such as autophagy in disease pathogenesis. Understanding the detailed mechanism of how autophagy and related hepatic factors play a role in disease pathogenesis will help build therapeutic targets for the treatment of various liver diseases. Noteworthy, many therapeutic activators and inhibitors are now available to modulate hepatic autophagy.
Do you have any advice for young scientists interested in pursuing a research career?
Biomedical research is fascinating. Follow your passion to understand the basics of disease pathogenesis. It is always fulfilling to get the answer for a basic, fundamental research question that will have a future or immediate translational impact.
- Choose well (Mentor, Project, and Place)
- Learn broadly.
- Build a network in your research arena gradually from your doctoral work.
And finally, if you could meet any scientist from the past, who would you meet and why?
Christian de Duve, the father of autophagy and lysosome biology. The discovery of lysosomes was the first step in understanding the autophagic intracellular degradation system. Recent studies show lysosomes as a metabolic signaling center, that can also function in the secretion of various hepatokines. Secretory hepatokines play a major pathogenic role in liver inflammation or fibrosis. Hence, targeting lysosomal secretion and hepatokines’ cargo could be potential therapeutic targets to treat diseases like PSC.
Select Publications by Dr. Khambu:
Khambu, B., Yan, S., Huda, N., & Yin, X. M. (2019). Role of High-Mobility Group Box-1 in Liver Pathogenesis. International journal of molecular sciences. https://doi.org/10.3390/ijms20215314
Khambu, B., Yan, S., Huda, N., Liu, G., & Yin, X. M. (2018). Autophagy in non-alcoholic fatty liver disease and alcoholic liver disease. Liver research. https://doi.org/10.1016/j.livres.2018.09.004
Khambu, B., Yan, S., Huda, N., Liu, G., & Yin, X. M. (2018). Homeostatic Role of Autophagy in Hepatocytes. Seminars in liver disease. https://doi.org/10.1055/s-0038-1669939
Khambu, B., Wang, L., Zhang, H., & Yin, X. M. (2017). The Activation and Function of Autophagy in Alcoholic Liver Disease. Current molecular pharmacology. https://doi.org/10.2174/1874467208666150817112654
Yan, S., Huda, N., Khambu, B., & Yin, X. M. (2017). Relevance of autophagy to fatty liver diseases and potential therapeutic applications. Amino acids. https://doi.org/10.1007/s00726-017-2429-y
Rare Genomics Institute BeHEARD Competition Contacts:
Sudheendra N. R. Rao
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