NSF CAREER Award for Examining sRNAs as Potential Disease Prevention

Jiahe Li

Jiahe Li, assistant professor, bioengineering (BioE), has been awarded a $636,000 National Science Foundation (NSF) CAREER Award, titled “Understanding and Harnessing Host-derived Small RNAs Against Opportunistic Pathogens,” to learn how to harness one of the body’s natural defense mechanisms to inhibit bad bacteria.

Humans and other vertebrates have various biological defenses against pathogens that enter their systems, from antibodies to antimicrobial peptides. Li’s research is one of the first in the world to consider how the mechanisms of extracellular small RNAs (sRNAs) can be leveraged to help control the spread of disease in the microbiome.

“Small RNAs are very short molecules, around 20–30 nucleotides as opposed to the thousands that make up mRNA vaccines,” says Li. “Some sRNAs that are secreted by hosts can enter bad bacteria within the microbiome in a specific way to inhibit it, thereby guarding against pathogens. Our research seeks to understand more about this process.”

By understanding more about how sRNAs function as inhibitors in the body, Li and his team hope first to identify more sRNAs that are capable of mediating antimicrobial effects on opportunistic bacteria, and then to translate this knowledge into potential drug therapies.

While there are many sRNAs secreted in the human body, Li and his team are looking at two specific ones as in vitro interaction models in this research. The first, Fusobacterium nucleatum, originates in the oral cavity and can drive periodontal disease; in addition, it can migrate into the gut and accelerate colon cancer. The second is Pseudomonas aeruginosa, which affects the lining of the lungs. It is one of the leading causes of hospital-acquired infections worldwide due to its ability to develop antibiotic-resistant biofilms.

“The ability to use sRNAs in this kind of direct approach at impeding only the bad bacteria could be preferable against treatment with antibiotics, which kill or inhibit both good and bad bacteria in the host’s microbiome,” says Li. “The overuse of antibiotics can also cause antibiotic resistance in which the treatment becomes less successful or even ineffective.”

In addition to the potential societal impact of the research itself, Li intends to use his CAREER grant to expand educational opportunities for students both near and far to increase interest in and access to STEM knowledge.

Li’s Advanced Therapeutics Lab involves undergraduate students at Northeastern from a range of backgrounds, including bioengineering, chemical engineering, biochemistry, and computer science. Li plans to widen these recruitment efforts to include students from nearby colleges without a strong research focus to broaden the educational impact of his work.

“Conducting research is a proven strategy to foster the development of interest for undergraduate students, not to mention the laboratory skills and independent critical thinking ability acquired,” says Li.

Building off the success of a remote collaboration with students and faculty at the University of Maine in 2020 and 2021, Li is using CAREER Award grant funds to develop low-cost biology kits and virtual teaching methods to reach students in remote areas. These efforts will help expand exposure to hands-on STEM learning in schools without the resources for these kinds of experiences.

Beginning this summer, Li’s lab will also participate in Northeastern’s Young Scholars Program (YSP), bringing underrepresented minority (URM) high school students to campus for hands-on lab experience to encourage careers in STEM. For the next five years, two URM students will each be paired with a senior graduate student from Li’s lab to improve their technical abilities, build professional skills, and increase their confidence regarding STEM career options.

Abstract source: NSF

Complex communities of microbes colonize all living creatures. These communities comprise a microbiome. Communication between the host and various microbiomes help to maintain human health. Disrupting this communication can lead to infection and disease. Recently, studies have implicated small RNA molecules (sRNA) as key communication molecules. Understanding how different types of sRNAs regulate pathogens in oral and respiratory systems is the focus of this project. The research program will be integrated with an education and outreach plan. These efforts will prepare under-represented high-school students and undergraduates to pursue careers in STEM. They will also integrate authentic hands-on experiments into undergraduate courses and develop low-cost biology kits and virtual teaching methods to reach students in remote areas.

This project will address the knowledge gap in understanding the roles played by host-derived extracellular sRNAs in host-microbiota interactions. There is a lack of enabling methodologies to unlock the functions of host sRNAs largely due to three limitations. First, native sRNAs are highly susceptible to degradation. Second, it is difficult to distinguish the origins of short sRNA fragments between host and bacteria. Third, host sRNAs are present inside bacteria at very low levels. The long-term project goal is to achieve in-depth understanding of host-derived sRNAs as a new class of defense molecules targeting opportunistic pathogens, and, furthermore, to repurpose host sRNAs as potential antimicrobial agents. To achieve this goal, this project will (1) optimize sRNA stability and functions by incorporating chemically modified nucleotides and define structure-function relationships, (2) employ structural modeling, bacterial genetics, and biochemical assays to dissect how host sRNAs are internalized by oral and airway opportunistic bacteria, and (3) develop a powerful methodology to uncover hitherto unknown host sRNAs with antimicrobial activities.

This award reflects NSF’s statutory mission and has been deemed worthy of support through evaluation using the Foundation’s intellectual merit and broader impacts review criteria.

Related Departments:Bioengineering