WMed researcher awarded $1.89 million NIH grant to study how 3D genome folding directs generation of diverse antibodies 

Dr. Yu Zhang
Yu Zhang, MD, PhD

Yu Zhang, MD, PhD, an assistant professor in the medical school’s Department of Investigative Medicine, studies V(D)J recombination, a critical process for the human immune system that produces a diverse repertoire of antibodies to ward off threats posed by microbial organisms.

In December, two years after Dr. Zhang joined WMed, her lab’s recent research landed a five-year, $1.89 million grant from the National Institutes of Health to investigate the key mechanisms of V(D)J recombination.

“V(D)J recombination needs to be properly directed, this is not only crucial for efficient antibody generation, but also important to prevent leukemias and lymphomas caused by aberrant V(D)J recombination activities”. Dr. Zhang said.

Our genome is folded into a hierarchy of structures to direct biological activities, including formation of multiple chromatin loops. V(D)J recombination cuts and pastes gene segments that often span large linear genomic distance and requires formation of long chromatin loops to promote the reaction. Many underlying molecular mechanisms remain unknown, Dr. Zhang said.

“This research aims to understand how the dynamic 3D genome folding process guides proper V(D)J recombination," Dr. Zhang said.

This NIH-funded research could help understand how our immune cells promote a diverse antibody repertoire, focus V(D)J recombination to proper “on-targets” and suppress tumorigenic “off-target” activity, Dr. Zhang said. This improved understanding of antibody generation can also help guide design of new animal models for vaccination. She also anticipates the research to have a broad impact on gene regulation mechanisms.

Dr. Zhang’s grant marks the third new R01 grant received by the medical school since WMed was founded in 2012. In all, the medical school has received $5.3 million in new NIH R01 grant funding since 2016. These grant application all originated from WMed, said Tom Rothstein, MD, PhD, chair of the medical school’s Department of Investigative Medicine. Dr. Rothstein’s lab received a five-year, $1.89 million NIH grant in January 2019 for a project titled “Human B1-like Cells and Pneumococcal Defense in the Elderly,” where he and his team are looking to pinpoint why the elderly are more susceptible to pneumococcal pneumonia and identify what role B-1 cells play in the decline in pneumococcal defense.

In September 2020, a research project headed by Dr. Nichol Holodick titled “Sex Determines Age-related Changes in the Repertoire and Function of Natural Antibodies Protective against Streptococcus pneumoniae with Increasing Age,” was supported with a four-year, $1.51 million NIH grant. Dr. Holodick studies a specific subset of white blood cells, B cells, that make proteins called antibodies, which are able to bind to and facilitate the clearance of bacteria. Her research focuses on the loss of protective antibodies against pneumococcal bacteria with advancing age and the role of sex in determining differences in protection from infection between males and females.

Dr. Rothstein said the medical school’s success with R01 grants points not only to the cleverness of the faculty that submitted the grants, but also, and significantly, to the intellectual and academic environment that has been created at the medical school by all faculty.

“I think this is credit not just to the junior faculty in my department who were the principal investigators on these grants, but it’s an important testament to the entire medical school,” Dr. Rothstein said. “You’ve got to have everything in place from multiple departments to create a foundation for academic investigation that provides intellectual and practical support from which emerges one, two and now three exciting, NIH-supported paths of investigation.”

Dr. Zhang, in particular, was successful in securing a R01 grant on her first application after recently becoming a faculty member, a highly unusual and notable achievement, Dr. Rothstein said. 

“Because she’s studying how antibodies are formed, that may very well relate to the pool of antibodies that are activated by vaccines,” Dr. Rothstein said. “Trying to understand what determines V(D)J recombination will lead to understanding what antibodies are available to respond to vaccination and someday we may be able to influence that. Beyond antibody repertoire and vaccination, Dr. Zhang’s work can also help elucidate the origins of leukemia, and it can help establish key principles of gene regulation.”