BUFFALO, N.Y. — Radiation therapy, a common treatment for some oral cancers, can leave a patient’s salivary glands so damaged that even talking is difficult. Meanwhile, diseases such as Sjogren’s, which eradicates moisture from many of the body’s glands, can compromise the amount of saliva created in the mouth and also hamper speech and swallowing.
“Imagine shoving 10 crackers in your mouth and trying to speak. You can’t,” explained Rose-Anne Romano, PhD, associate professor of oral biology at the University at Buffalo’s School of Dental Medicine. “That is what life is like for patients with salivary gland dysfunction.”
Through a $2.2 million, five-year grant renewal from the National Institute of Dental and Craniofacial Research (NIDCR) within the National Institutes of Health, Romano is hoping to help alleviate suffering for such patients.
Her co-principal investigator for the renewal grant is Satrajit Sinha, PhD, professor in the Department of Biochemistry in the Jacobs School of Medicine and Biomedical Sciences at UB.
Through the project, “Regulatory mechanisms that dictate stem and differentiated cell populations of the salivary gland,” they aim to understand how salivary glands develop, maintain and repair themselves after injury or from diseased states.
“I’m ecstatic that this grant was renewed,” Romano said. “We’ll gain more information and move this research forward with the ultimate goal of helping patients regenerate damaged glands.”
The two researchers have been long-term collaborators on grants and publications, along with co-mentorship of PhD students.
Last year, they published the paper, “Genetic Study of Elf5 and Ehf in the Mouse Salivary Gland,” that was featured on the cover of the March 2023 issue of the Journal of Dental Research (JDR) and also won the 2023 JDR Cover of the Year award.
The importance of certain proteins
With this new grant, they are primarily focusing on p63, a protein that regulates many cell activities. Specifically, they’re examining a version of p63 known as Delta Np63, which is crucial for the development and maintenance of salivary glands.
“Both of our labs have been at the forefront of studying p63 and have generated mouse models which have shown, that in the absence of p63, specifically the DeltaN variant, many organs and tissues such as the salivary glands fail to form,” Sinha said. “Understanding fundamental gene control mechanisms that direct tissue development and maturation will allow us to better treat human diseases where the organ — the salivary gland in this case — does not work efficiently.”
These processes involve stem or progenitor cells, which can renew themselves, or divide and become different types of cells needed for the gland to function, Romano explained.
“With the first grant, we were trying to understand if p63 is actually a stem cell marker and how p63 positive cells contributed to salivary gland development,” Romano said. “If it’s a stem cell, it’s got to give rise to the different cell types that make up the salivary gland. These cells survive about 180 days and then die, yet most people have an endless supply of saliva. This is because of stem cells and their role in the regeneration process. However, we still don’t know how this process occurs in the salivary gland.”
Branching morphogenesis and rejuvenation
In the first grant, Romano said they realized that these p63 expressing cells are really important.
“They maintain the gland and all of the epithelial cell types that make up the gland during adulthood and during embryogenesis when the gland is growing and first established,” Romano said. “We were the first to report that these p63 expressing stem cells can give rise to all the differentiated epithelial cells of the gland.”
They’ve realized that p63 has to work with other co-factors to exert its function.
In the second phase of this research, Romano and Sinha, with help from a handful of lab researchers and students, are trying to identify the other players in this process that help p63 do primarily what it needs to do, i.e., turn important genes on or off.
They also are studying the role of p63 in branching morphogenesis.
“Salivary glands are like mammary glands with all the associated branches,” she explained. “Mammary glands continuously produce milk during lactation. Their branched structures provide the increased surface area needed for producing large amounts of milk. In this respect, the salivary gland is no different except for the production of saliva.”
Sinha said that they hope that by learning about branching, they can biomedically engineer organs, such as the salivary gland.
By the end of the five-year project, Romano and Sinha will conduct a comprehensive analysis to figure out how p63 and its targets and co-regulators influence the signaling network in the salivary gland.
“This work is innovative because our use of sophisticated technologies to examine genomic and epigenetic mechanisms of gene regulation will lead to new discoveries into salivary gland organogenesis and regeneration,” Romano said.
The hope is to eventually implement these processes in human trials.
“Long term, we hope that our studies with the NIH-funded grant will facilitate better design and fabrication of bioengineered glands and stem cell replacement therapies,” Sinha said. “We hope this becomes a reality within the next five to ten years.”
Research reported in this publication was supported by the National Institute Of Dental and Craniofacial Research of the National Institutes of Health under Award Number R01DE027660.
