CROSSTALKS BETWEEN IMMUNITY, DNA REPAIR, AND THE MICROBIOTA – NEW WINDOWS FOR FUTURE THERAPIES?

The immune system and the DNA repair system are fundamental for life. Hence, defects in these systems lie at the core of most health conditions. Much of our current understanding of these systems is based on decades of research looking at them. We have found that these systems are interdependent and modulated by the microbiota.

Further, we have identified regulatory components linking immunity, DNA repair, and the microbiota.

Key among these include the immune DNA receptors, cGAS, and ALRs.cGAS and ALRs are best known for their role in alerting our immune system to the presence of foreign DNA in the cell, for example, upon infection. We found that they also regulate DNA repair.

This dual function indicates a possible use of cGAS and ALRs as targets for manipulating the immune and DNA repair responses in disease management.

We have identified a small molecule inhibitor of cGAS and ALRs and found it can suppress inflammation while promoting DNA repair.

In this project, we will investigate the role of cGAS and ALRs in aging-associated inflammation and the possibility of using the inhibitor of cGAS and ALRs as treatment. We will also conduct mechanistic studies into how the microbiota modulates the immune and DNA repair systems. We will employ genetic mouse and cell culture models for accelerated aging.

We expect this project to generate new information relevant to finding new therapies against complex health conditions such as aging-associated health decline.