University of California School of Medicine researchers have been awarded nearly $ 9 million to fund two multi-institutional research projects that use human pluripotent stem cells, CRISPR and human organoids to dissect beta-cell damage and create a human cell model of type 1 diabetes to identify elusive cellular actions that lead until the onset of illness.
We use technology that, for the first time, allows us to create human conditions that mimic type 1 diabetes in culture to understand the mechanism or genes by which beta cells are killed. We hope we can create the information we need to help beta cells survive in people living with type 1. diabetes. "
Maike Sander, MD, PhD, Professor in the Department of Pediatrics and Cell and Molecular Medicine at UC San Diego School of Medicine and Principal Investigator for both scholarships
Two multi-year special statutory fellowships from the National Institute of Diabetes, Digestive and Kidney Diseases, part of the National Institutes of Health (NIH), help build on ongoing research into type 1 diabetes, an autoimmune disease that destroys pancreatic beta cells and affects more than one million people in the United States . The pancreatic beta cells, which are in groups called Langerhans islets, help maintain normal blood glucose levels by producing the hormone insulin – the main regulator of energy (glucose). Damage and loss of beta cells reduce insulin production, leading to type 1 and 2 diabetes.
The $ 3.8 million grant was jointly led by Dr. Sander and Kyle Gaulton, Assistant Professor in the Department of Pediatrics and the Pediatric Diabetes Research Center, to decipher the function of genetic risk-related genes for type 1 diabetes using a high-resolution map reference pancreatic cells. Sander, Gaulton and his colleagues are designing the map after receiving an NIH grant in 2018.
"A unique aspect of this project is to determine the effect of pancreatic beta cells on type 1 diabetes through a combination of your genes and your environment," said Gaulton, who brings expertise in the genetics and genomics of diabetes to the project. "Our goal is to identify genes that protect beta cells from immune responses that arise during the development of type 1 diabetes and that may represent new therapeutic targets in preventing disease."
After identifying genes associated with beta cell function, a team including PhD Prashant Mali, Assistant Professor in the Department of Bioengineering at UC San Diego Jacob Engineering Engineering, Wenxian Fu, PhD, Assistant Professor in the Department of Pediatrics and Diabetes Pediatrics Research Center, and Dr. Graham McVicker, an assistant professor at the Salk Institute, will use CRISPR to check which genes promote cellular survival and which cause cell death.
This information can then be tested using an islet on a chip (human organoid) that was developed with a second $ 5.1 million NIH grant to study the immune attack against beta cells in the plate. Human organoids are miniaturized, 3D versions of organs.
In this case, human induced pluripotent stem cells (hiPSCs) from persons with type 1 diabetes are converted to beta cells and support cells in the laboratory to create a human island organoid. Sander collaborates with Karen Christman, Ph.D., Professor in the Department of Bioengineering, Ph.D. Luc Teyton, Professor at the Department of Immunology and Microbiology at Scripps Research, Steven George, MD, Professor at the Chair of Bioengineering at UC Davis and Christopher CW Hughes, PhD, Professor at the Chair of Molecular Biology and Biochemistry at UC Irvine.
At UC Irvine, the Hughes lab created an organic chip that allows living blood vessels to provide nutrients to tissues that grow in the lab.
"We grow human islets in a culture that supports (i.e. feeds on) perfused blood vessels. All organs in the body receive their nutrients through the blood vessels, and we capture this process in the lab," Hughes said. "Under these conditions, we expect the islets to behave much more like they did in the flesh than we did to breed them using standard procedures, which have not changed much in the last 30 years."
Immune cells from the blood of the same person whose hiPSC was used to induce beta cells in the human organoid will be brought into the organoid to look at the immune system's response to the beta cells.
"We will activate and deactivate genes that we think are involved in whether the beta cells are living or dying. We want to know what causes the attack on the beta cells because no one has been able to identify them," said Sander, who is also director of the Pediatric Research Center for diabetes, co-director of the Diabetes Center at the Institute of Engineering Medicine and a member of the Sanford Stem Cell Clinical Center. "We are aware that people living with type 1 may still have beta cells. If we can save those cells, we may be able to help manage blood glucose and provide clinical improvement."
University of California School of Medicine, San Diego