TSRI Awarded $11 Million Grant Renewal by NIAID for Long-Running Study of Immunity, Inflammation

By Jim Schnabel

The Scripps Research Institute (TSRI) has been awarded a five-year, $11.2 million grant from the National Institute for Allergic and Infectious Diseases (NIAID), part of the National Institutes of Health. The award is a continuation of support for a long-running, collaborative project to reveal the detailed workings of the mammalian immune system.

The principal investigator for the project is Richard J. Ulevitch, a professor in TSRI’s Department of Immunology. The chief research collaborators are Alan A. Aderem of the Center for Infectious Disease Research in Seattle, Garry P. Nolan of Stanford University, and Bruce A. Beutler, who helped co-found the project while at TSRI but is now at the University of Texas Southwestern.

The project has been supported by NIAID since its inception in 2002, and by the end of the new grant cycle will have run for two decades. Its long run and high level of funding reflect the resources and effort needed to realize its ambitious goals—and have been justified by a steady production of seminal findings.

“It is one of the most productive large-scale science grants that NIAID funds,” said Ulevitch.

The project’s major aim has been to map the molecular and cellular interactions that underlie immunity and inflammation in health and disease. That in turn should enable the invention of better drugs and vaccines for infections, inflammatory diseases, and other immune-related ailments.

A large part of the research involves a strategy known as forward genetics, in which the scientists—using mutagenic chemicals in this case—create random DNA mutations in a population of test animals. They screen the animals for resulting immune-related changes (phenotypes), and when they find significant ones, use nex-gen DNA sequencing technology to identify the mutated genes that caused the phenotypes.

The researchers mine the existing literature on gene and protein function, and apply the statistical and computational methods of systems biology, to connect these gene-phenotype data points and thereby map the functional networks that underlie immunity.

Because forward genetics studies typically require the breeding of multiple generations of large numbers of animals to obtain solid results, they are apt to use very small, fast-breeding lab animals such as Drosophila fruit flies. By contrast, this project is aimed at probing the mysteries of mammalian immunity, and thus requires mice—thousands of them, mostly in a colony now maintained by Beutler at UT-Southwestern.

“It has to be one of the largest mouse colonies in the US,” Ulevitch said.

The immune-related gene and phenotype details uncovered by the project are kept in large databases that are available online, for example at https://mutagenetix.utsouthwestern.edu/.

“Unlike a lot of science, this is not a hypothesis-driven project,” said Ulevitch. “It’s really a large-scale program to provide information on the immune system as a basic resource for other investigators.”

In addition to expanding their datasets, scientists on the project also have been publishing a steady stream of noteworthy findings in immunology-related journals, for example concerning proteins newly discovered to have important roles in immunity.

The project’s focus initially was on the “innate” immune system: the network of immune molecules and cells—such as macrophages—that evolutionarily predates the more antigen-specific “adaptive” immune system of B-cells and T-cells. Now, according to Ulevitch, it is beginning to focus as well on the important interface between innate and adaptive immunity—where key events in healthy immunity, pathological autoimmunity, and immune deficiency can occur.

Thanks in part to advances in DNA sequencing, computational approaches and novel optical of living cells the work is defining immune pathways and networks faster than ever.

“At the outset of this project it could take years of work to go from knowing that you have a transmissible mutation that causes a phenotype to identifying that mutation,” Ulevitch said. “Today with next-gen sequencing and our combination of systems biology and forward genetics, that part of the process can take less than a day once the transmissible phenotype is fully characterized.”

The grant number is U19AI100627.

Send comments to: press[at]scripps.edu

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