Weil Institute K12 scholar awarded over $500,000 to study how cholesterol affects sepsis immune response
Initial research finds inhibiting cholesterol production protects against sepsis toxicity.
Contact:
Katelyn Murphy
Marketing Communications Specialist, Weil Institute
mukately@med.umich.edu
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ANN ARBOR, MI – Dr. Vinitha Jacob, Clinical Assistant Professor of Emergency Medicine at the University of Michigan, has received a three-year, $583,000 K08 grant through the National Institute of General Medical Sciences (NIGMS) of the National Institutes of Health (NIH) to pursue a novel pathway for transforming treatment of sepsis. Dr. Jacob credits this award to the support and guidance of her mentors and advisors, and to the training she received through the K12 Emergency Medicine Research Career Development Program at the University’s Max Harry Weil Institute for Critical Care Research and Innovation.
The Sepsis-Cholesterol Connection
Sepsis is a life-threatening medical emergency that occurs when the body’s dysregulated response to an infection causes uncontrolled inflammation and widespread organ damage. Currently, the only way to treat sepsis is to administer antibiotics that target the bacteria behind the initial infection; however, increased usage of antibiotics has led to growing concerns over the development of medication-resistant superbugs. Additionally, nothing specific is currently available to regulate the body’s uncontrolled response to infection. As a result of these factors, there exists a critical need for new therapeutics that can alleviate sepsis toxicity while also supporting the body’s natural recovery processes.
The clinical problem of sepsis had long been an area of interest for Dr. Jacob. Her path to finding a potential cure eventually led her to the University of Michigan and to the Weil Institute’s Emergency Medicine Career Development Training Program. Building upon her previous work with collaborators from the University of Florida and the University of California Los Angeles, Dr. Jacob examined a zebrafish model of uncontrolled inflammation, which recapitulated features of sepsis, alongside data from human sepsis patients. The team found that in both the fish and human data, cholesterol metabolism genes were highly upregulated. Specifically, a gene called DHCR7, which catalyzes the last step of cholesterol production, was shown to be significantly upregulated in both human sepsis patients and in the zebrafish model of uncontrolled inflammation.
"Currently, we treat sepsis supportively with broad-spectrum antibiotics, but we don’t really do anything for the dysregulated immune response. We envision giving this gene inhibitor to humans, which could enable the host to respond to infection in a more controlled fashion."
Vinitha Jacob, MD, PhD
Clinical Assistant Professor, Emergency Medicine
University of Michigan
“It has been consistently shown that there is a significant association with cholesterol levels and sepsis outcomes in humans,” said Dr. Jacob. “We don’t know these mechanisms yet, but in our zebrafish models those pathways were among the top most upregulated pathways and were on par with the inflammation-related genes that we would normally expect. That was really fascinating to us.”
Intrigued by this finding, Dr. Jacob applied a DHCR7-specific gene inhibitor to her zebrafish model and discovered that it completely rescued the fish from endotoxemic death. Now, utilizing the NIH funding and K12 program, she aims to determine the mechanisms behind this protection and to understand whether these effects can be reproduced in mammals. She also seeks to identify clinically available DHCR7 inhibitors that could be potentially repurposed for use in humans.
While the new study is only just beginning, the knowledge Dr. Jacob and her team gain could have significant impact on the management of sepsis and other inflammatory disorders.
“Currently, we treat sepsis supportively with broad-spectrum antibiotics, but we don’t really do anything for the dysregulated immune response,” said Dr. Jacob. “If all of this pans out, we envision giving this gene inhibitor to humans, which could enable the host to respond to infection in a more controlled fashion.”
A Career Development Capstone
Operating from 2016 to 2021 through a grant from the NIH, and administered through the Weil Institute, the K12 program matched participants with mentorship teams comprised of senior clinician-scientists from fields such as emergency medicine, pulmonary and critical care, engineering, and biostatistics. The mentors helped the scholars design personal development plans that included academic courses as well as training in clinical trial design, leadership, grant writing and data management. The goal of Weil Institute K12 training was for participants to obtain individual K or R01 funding by the end of their third year, marking their transition into productive emergency medicine research careers.
Dr. Jacob’s mentors and advisors included Dr. Jordan Shavit (Cellular and Molecular Biology, Human Genetics), Dr. Robert Dickson (Internal Medicine, Pulmonary and Critical Care Medicine), Dr. Anna Schwendeman (Pharmaceutical Sciences), and Dr. Kathleen Stringer (Clinical Pharmacy) from the University of Michigan; Dr. Faheem Guirgis (Emergency Medicine) from the University of Florida; and Dr. Srinivasa Reddy (Medicine, Molecular and Medical Pharmacology) from the University of California Los Angeles.
“Team science is clearly the only way to conquer diseases such as sepsis that pose tremendous challenge to human health and lives,” said Dr. Reddy. “I strongly believe that Dr. Jacob’s work in the coming years will make significant contributions to the discovery of novel therapeutic agents for treating sepsis.”
“Dr. Jacob’s zebrafish model was a very exciting way to test and validate the findings we were seeing in humans in a mechanistic model with the potential for high throughput drug screening,” said Dr. Guirgis. “This advancement for our collective work studying cholesterol and lipid metabolism in sepsis was a huge step forward, and we are excited to work with Dr. Jacob and her lab and team to advance our understanding of cholesterol metabolism in sepsis and new potential therapies.”
Dr. Dickson and Dr. Stringer, who both serve as deputy directors of the Weil Institute, also shared their thoughts on the value and potential impact of Dr. Jacob’s research.
“By developing and leveraging this exciting zebrafish model, Dr. Jacob has provided the field with a way to identify critical, evolutionarily conserved pathways that contribute to sepsis, and test hundreds or thousands of potential treatments,” said Dr. Dickson. “This is precisely the kind of innovation that the field of critical care research needs, and we are lucky to have her taking full advantage of the resources of UM and the Weil Institute."
“An added value of this model is that it can be ‘scaled up’ for testing in our swine model of sepsis. This is very exciting, as it will make her findings highly translatable and will create new opportunities for her and Weil Institute collaborators,” said Dr. Stringer.
“I felt like this was my opportunity to get things off the ground,” said Dr. Jacob. “Even though Michigan was far away from where I was originally, I took the leap and came here because of all the support I was offered through this program. Having all of these people reading my grant application and being generous with their time and resources really helped me to get to this point.”
Further Reading
DHCR7 Expression Predicts Poor Outcomes and Mortality from Sepsis; Critical care explorations, https://doi.org/10.1097/CCE.0000000000000929
About the Weil Institute
The team at the Max Harry Weil Institute for Critical Care Research and Innovation is dedicated to pushing the leading edge of research to develop new technologies and novel therapies for the most critically ill and injured patients. Through a unique formula of innovation, integration and entrepreneurship that was first imagined by Weil, their multi-disciplinary teams of health providers, basic scientists, engineers, data scientists, commercialization coaches, donors and industry partners are taking a boundless approach to re-imagining every aspect of critical care medicine. For more information, visit weilinstitute.med.umich.edu.