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Karen Jonscher, PhD

Developmental Programming of NASH in Offspring of Obese Mothers—Critical Role of the Liver Microphage

Dr. Jonscher is interested in understanding the early origins of obesity and cardiometabolic disease, and how exposure to excess fat in utero might increase the risk of adult disease in developing infants. Dr. Jonscher uses a mouse model of nonalcoholic fatty liver disease (NAFLD), which is the number one liver disease worldwide in children and adults. Increasingly, people who suffer from this disease progress to NASH (non-alcoholic steatohepatitis) , the more severe form, with high rates of mortality due to cardiovascular disease and lack of available treatments. 

Dr. Jonscher’s research has shown that treating obese mice during pregnancy and lactation with an antioxidant, pyrroloquinoline quinone (PQQ), can protect their offspring from progression toward NASH in adulthood. Her goal is to understand how, on the cellular level, PQQ provides this protective effect. Furthermore, infants born to obese mothers have increased liver fat and, in later life, are at a higher risk of progressing to obesity. Ultimately, Dr. Jonscher hopes PQQ might be used to protect offspring of obese pregnancy and interrupt the vicious cycle of metabolic disease between mother and baby.
We spoke to Dr. Jonscher at length about her life and work.

When you were young, what did you envision yourself doing when you grew up?

It’s a long story! When I was young I wanted to be a novelist. Specifically, I wanted to write about espionage. I also wanted to write screenplays. When I was in college, pursuing a degree in political science, I began to wonder how I would be able to survive if I couldn't get published. I decided to take a step back and reassess. I quit school and started working in various jobs—temp jobs, secretarial, waitressing. After a couple of years, I decided I needed to go back to school and get a degree and, since I like to travel, figured I should go for international business and then go to law school. When I took my first math class I found out that suddenly, I could do math! This was a big surprise. I took some career assessments and they all said I should be an engineer. I applied to the School of Engineering and, while I was working on the pre-requisites, declared as a Physics major (mainly because a friend was doing the same). Next surprise—I loved physics! After much advisement from my professors, I majored in Engineering Physics at Boulder and then went to graduate school at CalTech where I pursued a Ph.D. in Applied Physics. Although I was very interested in multi-wave lasers and holography, the professor with whom I wanted to work changed his focus. Actually, as a woman, I had a very difficult time finding a mentor to work with in my department. Finally, I went outside of my department and began my Ph.D. studies with Drs. Lee Hood and John Yates from the Biology Department. My work involved building mass spectrometers and ionization sources that were used in the newly developing field of proteomics. I went on to postdoc in Boulder, developing methods for large-scale proteomics analyses then came to Denver where I managed a proteomics core facility for a number of years. Wanting to contribute more, I applied for and was awarded a K 25 Career Transition Award that allowed me to learn about cell biology and physiology and to begin developing a model for my current research focused on the early origins of fatty liver disease and cellular mechanisms involved.

If you had to summarize your research briefly, how would you describe it?

My research using a mouse model investigates the effect of a mother's obesity and consumption of a high-fat diet on her offspring's risk for severe liver disease, and protective effects of a novel and potent anti-oxidant, pyrroloquinoline quinone (PQQ). We have found that adult offspring of mice fed a Western-style diet (high in fat, sugar, and cholesterol) have fatty livers with inflammation and fibrosis. If we treat the mothers with PQQ during gestation and lactation, the offspring are protected from fatty liver, inflammation, and fibrosis—even if they are not exposed to PQQ except through their mothers in early life. We are working on understanding the mechanisms by which this may work, and focusing on a potential role for macrophages, which are cells involved in promoting fibrosis or liver repair, depending on their metabolism. We think Western-style diet promotes a pro-fibrotic metabolic state and PQQ may be protective.

What are the real-world applications for your work? In other words, how can it help people?

PQQ is a dietary supplement that is available over-the-counter. It has been tested in humans and has proven safe. This compound could potentially be used as a therapeutic. We are looking into the potential for patenting applications for this work, so I can’t be too specific about ideas yet.

What are your plans for the future of your research?

As this work progresses, we are using mouse models to better understand the molecular mechanisms underlying developmental programming of fatty liver disease and how PQQ works to prevent inflammation and fibrosis. We then want to move into the clinical realm. Our current studies in mice will help inform design of future studies in humans, particularly those involving pregnant women and their babies. Another area of interest for me is spaceflight. We are seeking funding now to investigate utility of PQQ as countermeasure to protect from oxidative stress using a ground-based model for spaceflight. If that is successful, I hope one day that astronauts will take PQQ as they travel to Mars!