Over the past decade, University at Buffalo chemists have made steady progress on developing biochemical tools that can be deployed inside living cells to study how pharmaceuticals affect those cells’ inner workings.
A new $2 million grant from the National Institute of General Medical Sciences, part of the National Institutes of Health, will enable the researchers to take their work to the next level — including by testing these new tools inside cells.
Eventually, the research could facilitate development of therapies for the treatment of diseases such as diabetes, depression and osteoporosis.
“Our project utilizes chemistry as a research tool to study biological problems inside living cells,” says lead scientist Qing Lin, PhD, professor of chemistry in the UB College of Arts and Sciences. “Even when a drug works in treating disease, we often don’t understand the details of how it does its job. The tools we are developing will hopefully help to fill this gap in knowledge.”
The focus of Lin’s work is cellular receptors — specialized protein molecules that protrude from the surface of human cells. When hormones or pharmaceuticals bind to these receptors, the receptors become activated, triggering a chain of events inside the cells that cause the cells to take specific actions, such as secreting insulin.
Lin’s lab is developing tools to study, firstly, how cellular receptors change shape when they’re activated, and, secondly, how molecules inside human cells respond when a receptor is activated.
To accomplish the first task, the researchers are creating fluorescent probes that can be attached to specific parts of cellular receptors to monitor how the receptors change shape upon activation. To achieve the second objective, the team is creating genetically engineered cellular receptors that “trap” targeted molecules, enabling scientists to understand which molecules inside a human cell interact with an activated receptor (this early recruitment is an important first step in the cascading chain of events that takes place after a receptor is activated).
In short, Lin says, “We are developing tools for making possible real-time measurements related to molecular events that take place inside living cells when receptors are activated.”
This NIH-supported research focuses on a specific class of receptors called class B G protein-coupled receptors (GPCRs) that play a role in diseases including diabetes, depression and osteoporosis.
But, if successful, the methods Lin is developing could be adapted to study other kinds of cellular receptors as well, he said.
“Our tools will enable scientists to monitor what happens inside a cell when a receptor is activated in real time,” Lin says. “This is very valuable because different molecules can activate the same receptor in different ways and trigger different downstream signaling events within cells, which may produce discrete physiological responses.”
Lin has long had an interest in applying his expertise in chemistry to problems in biology. Among other activities, he is founder of Transira Therapeutics, a UB spinoff and drug development company whose first product under development is a diabetes drug that acts on class B GPCRs.