SEPTEMBER 28, 2021 — Brain and stem cell researchers from The University of Texas at San Antonio have secured $12.5 million in funding over five years from the National Institutes of Health through the NIH BRAIN Initiative to advance new methods for studying genetic brain disorders. The results of their study could have a significant impact toward one day treating or eliminating neurological diseases such as epilepsy, Alzheimer’s disease and more.
Brian Hermann, associate professor in the university’s newly formed Department of Neuroscience, Developmental and Regenerative Biology, is the lead principal investigator. He’ll be working with Jenny Hsieh, professor and department chair, the Semmes Foundation Distinguished Chair in Cell Biology, department chair and director of the Brain Health Consortium; John McCarrey, professor and Kleberg Distinguished University Chair in Cellular and Molecular Biology and co-director of the UTSA Institute of Regenerative Medicine; and Christopher Navara, director of the UTSA Stem Cell Core and associate professor of research. The team will contribute their scientific expertise to different aspects of the study to optimize a new method for producing marmosets that have genetic changes (aka transgenic marmosets) that can be used to study human brain disease.
Hermann will lead the testing of a novel approach to produce transgenic marmoset sperm using genetically “edited” induced marmoset pluripotent stem cells. In this first phase of the research, Navara and the UTSA Stem Cell Core will produce new stem cells and use a technique (called Clustered Regularly Interspaced Short Palindromic Repeats aka CRISPR/Cas9 editing) to make genetic alterations in the cells.
The research team will collaborate with Kotaro Sasaki from the University of Pennsylvania, who is an expert in converting human and primate stem cells into cells that can produce sperm. Sasaki will work on optimizing his techniques for this project, working directly with the research team to bring the technology to UTSA.
Hermann will then use the induced marmoset male germ cells to produce sperm. The team expects that marmoset offspring could eventually be produced from the edited sperm during normal reproduction. If so, the offspring would become valuable models for studies of various human brain diseases.
“What’s truly unique about our research is our approach to making transgenic marmosets,” Hermann said. “We will make genetic changes in male germ cells that can then give rise to sperm to pass on the genetic changes that will allow us to study human brain disease in offspring.”
Hermann and McCarrey are frequent collaborators and together have worked on many aspects of spermatogenesis as it relates to stem cell biology, regenerative medicine, and precision therapeutics. McCarrey’s lab will work with Hermann’s lab on verifying the marmoset male cells produced in a petri dish match the ones in the body using cutting-edge technology in the Genomics Core.
“We have assembled and cultivated advanced expertise within many UTSA disciplines. Combined with the strong relationships with our external research partners, UTSA-led teams can tackle complex, transdisciplinary inquiries posed by our funding agencies using unique methodologies, such as spermatogonial transplantation, in this particular application,” McCarrey explained. “No one lab, no one person could do it, but with each doing their part, we can do this together.”
The Hsieh laboratory uses pluripotent stem cells to evaluate the role of genetic mutations in epilepsy and neurodegenerative disorders, ultimately for precision medicine. The lab's researchers’ goal is to develop novel strategies to treat or prevent neurological disorders such as acquired and genetic forms of epilepsy or neurodegenerative disorders like Alzheimer's disease. For this research study, the Hsieh lab will focus on mutations in gene encoding the ARX protein which are relevant to epilepsy and will model using 3D brain organoids in a petri dish.
“One of the most distinctive features of humans as a species is the expanded and more complex cortex. The ability to generate 3D brain organoids from induced pluripotent stem cells allows us to study genetic brain disorders that were previously inaccessible,” Hsieh said. “We will create marmoset brain organoids from gene edited cj-iPSCs as a first step in the path to use the marmoset as a powerful model for basic brain mechanisms. Ultimately, we hope to tap into the marmosets’ behavioral and cognitive capacities, which is more like that of humans. That would be very exciting.”
The UTSA research team is also partnering with Corinna Ross at the Texas Biomedical Research Institute through their Southwest National Primate Research Center (SNPRC) to facilitate the production of sperm from germ cells produced in the laboratory. When marmoset offspring bearing genetic changes are developed, SNPRC will be integral to monitoring the genetically altered marmosets to identify neurological effects during their lifespan. This study is an important step toward gaining greater insight into brain diseases that have been otherwise difficult to treat or cure.
"This type of research—undertaken by Dr. Hermann and the transdisciplinary team which has been assembled—exemplifies the innovative and bold approaches for which UTSA is becoming known,” explained Bernard Arulanandam, UTSA’s vice president for research, economic development, and knowledge enterprise. “This is one of the largest NIH research awards ever received by the institution and is an endorsement of the contributions by our researchers to our collective knowledge base.”
UTSA is an urban serving research university that is committed to tackling society’s grand challenges. Its academic and research specialties include health, cybersecurity, fundamental futures and social-economic transformation.
This research is supported by the National Institute on Drug Abuse of the National Institutes of Health under award number U01DA054170. The content presented in this release is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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