Molecular and Functional Characterisation of Z-nucleic Acid-induced Signalling

This project aims to elucidate the mechanisms of ZBP1 activation by Z-nucleic acids to inform therapeutic strategies for modulating immune responses in autoinflammation, antiviral, and anticancer contexts.

Subsidie
€ 1.983.531
2024

Projectdetails

Introduction

Nucleic acids are potent activators of an immune response. Z-nucleic acids are poorly defined and thermodynamically unstable conformers of double-stranded RNA/DNA helices. Recently, others and our group showed that Z-nucleic acids are recognised by the nucleic acid sensor ZBP1, thereby inducing an antiviral immune response.

ZBP1 Activation and Implications

Activation of ZBP1 has also been shown to induce anticancer immunity, and it is becoming clear that chronic engagement of ZBP1 by endogenous Z-nucleic acids causes autoinflammatory pathology.

On top of that, a remarkably diverse set of cellular insults, ranging from pathogens and chemicals to genetic mutations, trigger ZBP1 activation. Despite its relevance in these important (patho)physiological events, knowledge on the fundamental principles that govern Z-nucleic acid-induced ZBP1 signalling is lacking.

Research Proposal

I here propose that ZBP1 perceives these widely different disturbances in cellular physiology by detecting the increased intracellular concentrations of Z-nucleic acids. Based on a newly developed ZBP1 activation model and using nanopore sequencing, structural biology, and chemical or genetic perturbation methods, we will:

  1. Characterise the molecular mechanisms that regulate Z-nucleic acid levels.
  2. Determine the biophysical determinants of ZBP1 activation.
  3. Map the ZBP1 downstream signalling network.
  4. Functionally validate our novel findings in cellular and in vivo models of ZBP1 activation.

Future Implications

The resulting detailed mechanistic understanding of ZBP1 function from single molecule to organism will enable us to develop future strategies for therapeutic interference with ZBP1-mediated immune responses, either negatively, to resolve autoinflammation, or positively, to promote antiviral or anticancer immunity.

Financiële details & Tijdlijn

Financiële details

Subsidiebedrag€ 1.983.531
Totale projectbegroting€ 1.983.531

Tijdlijn

Startdatum1-4-2024
Einddatum31-3-2029
Subsidiejaar2024

Partners & Locaties

Projectpartners

  • UNIVERSITEIT GENTpenvoerder

Land(en)

Belgium

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