Altered brain-periphery crosstalk as a key pathomechanism for high-risk phenotypes in humans

Introduction

Diabetes is a leading cause of morbidity and mortality worldwide. In our fight against the diabetes pandemic, my team and I recently identified subgroups of humans that are predictive of future life-threatening complications even before diabetes onset. Classification into these new risk groups is currently purely based on extensive phenotyping; yet, the underlying mechanisms are unclear.

Background

Of note, phenotypes of very high-risk persons are highly reminiscent of those from subjects with altered periphery-brain communication. I will combine ground-breaking experimental research in humans with the latest data analysis approaches to delineate the causal relationship between altered brain-periphery communication and very high-risk phenotypes.

Aim 1: Brain-Periphery Communication Disturbances

The 1st aim will reveal disturbances in the brain-periphery communication in high-risk persons. I will:

1. Identify differences in the transduction of neuronal signals to the target organs.
2. Discover regulators from the brain to the periphery.
3. Elucidate the regulation of underlying pathways.

Aim 2: Signalling from Periphery to Brain

The 2nd aim will clarify signalling from the periphery to the brain. I will:

1. Unravel the dynamic interaction between insulin and gut-derived hormones on the brain.
2. Identify signalling patterns that inform the brain about food intake and determine disturbances thereof in high-risk persons.
3. Non-invasively characterize postprandial molecular responses in neurons.

Aim 3: Non-Invasive Identification of High-Risk Persons

The 3rd aim develops a novel, non-invasive approach to identify high-risk persons by their altered brain-periphery communication. It will apply the above-generated knowledge to develop an algorithm-based integration of health data.

Conclusion

Ultimately, my project will innovatively define the impact of altered brain-periphery crosstalk in the development of clinically relevant high-risk groups. It will set the groundwork for novel approaches that optimize prevention and treatment of major complications and thereby improve future health, way beyond what is achieved by current approaches.