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; however, 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 groundbreaking 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

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

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, thereby improving future health, way beyond what is achieved by current approaches.