Alessio Accardi, professor of physiology and biophysics in anesthesiology at Weill Cornell Medicine, has been awarded a five-year, $2.7 million grant by the National Institute of General Medical Sciences (NIGMS), part of the National Institutes of Health (NIH), for fundamental research on cell membrane proteins that have critical roles in biology and are involved in numerous human diseases.

The grant is a highly sought-after MIRA (Maximizing Investigators’ Research Award), also known as an R35 grant. It is meant to provide long-term support for a laboratory as it investigates broad scientific questions, reducing the usual burden of grant proposal submissions and, compared with the standard R01 grant, allowing greater flexibility of aims and approaches.

“With this kind of grant, one has the freedom to pursue broad investigations within one’s area of expertise, and one can change direction as new findings arise,” said Accardi, who is also a professor of biochemistry at Weill Cornell Medicine. “We are excited to see in which new directions our research will take us. The flexibility to pursue new and unexpected findings is one of the reasons why I’m very grateful to have this award.”

Accardi studies proteins that mediate the movement of molecules across cell membranes, including ion-channel proteins, transporter proteins and scramblase proteins. These proteins are involved in brain-cell activity, muscle-cell contractions, the secretion of hormones and other signaling molecules, blood coagulation, repair or programmed self-destruction of damaged cells, and hundreds of other functions, often critical for human health.

This area of research can be very challenging, in part because membrane proteins typically can’t be studied in isolation – their inherently loose, fragile structures need to be anchored, as they are in nature, within cell membrane or membrane-like material. Moreover, the cell membrane is made of fat-related molecules called lipids, and lipid biology is notoriously complex and far from being thoroughly understood.

Nevertheless, Accardi and his team have been making steady progress in multiple directions. In a study in Nature Communications in 2022, they showed in near-atomic scale detail how the important TMEM16 family of scramblase proteins alters membrane structure; in so doing, they overturned what had long been the consensus model of TMEM16’s mechanism of action.

Under the new funding award, the Accardi lab will continue to elucidate the structures and functions of TMEM16 scramblases as well as a family of transmembrane channels and transporters called CLC proteins. Mutations affecting these have been implicated in a variety of genetic disorders, which have remained untreatable because of the lack of understanding of the underlying mechanisms.

“Our goal under this new grant,” Accardi said, “is simply to determine in detail how TMEM16s and CLCs normally work, and how disease-linked mutations disrupt their normal workings.”

Jim Schnabel is a freelance writer for Weill Cornell Medicine.