NTase Products and Cyclic Nucleotide Signalling

Introduction

Survival of a cell depends on its ability to receive and process information coming from the environment. Second messengers are the key transmitters of information that rapidly amplify the signal inside the cell. Cyclic nucleotides (CNs) are the most diversified category of second messengers and are found in all organisms modulating diverse pathways.

Background

CNs are best studied in bacteria, where they have a variety of biological functions. In humans, the only described cyclic di-nucleotide is cGAMP, which elicits an antiviral immune response. cGAMP is rapidly emerging as a promising drug candidate in, e.g., cancer immunotherapy.

Hypothesis

I hypothesize that additional CNs contribute to yet uncharacterized pathways in humans, and my aim is to discover novel CNs and their signalling pathways. CNs are synthesized by nucleotidyltransferases (NTases), and many human NTases remain uncharacterized due to the lack of activity in the absence of the cognate ligand.

Project Aim

This project aims to reveal the molecular function of uncharacterized NTases and to discover novel CN signalling pathways in humans in immune and non-immune-related areas of biology.

Objectives

I will focus on the following objectives:

1. Objective ❶: Activation of as yet uncharacterized NTases.
2. Objective ❷: Identification of CN signalling pathways involved in immune responses and beyond.

Expected Outcomes

The proposed experiments will provide me with candidates and precedence for CN signalling in humans other than cGAMP. The concept that yet uncharacterized CNs are involved in immune signalling as well as other pathways is highly innovative.

Significance

Together, the well-studied activities in bacteria and the overall conservation of NTases in humans further support the fundamental involvement of CN signalling in humans. My proposed research will open up conceptually new modes of regulation in human biology, reveal novel signalling pathways, and in the long term, contribute to new therapeutic options using CNs as drugs.