Neuro-immune regulation of type 1 diabetes onset in a dynamic framework

The goal of this proposal is to understand the involvement of sympathetic nervous signaling during onset of type 1 diabetes mellitus (T1D) using an approach which gathers mechanistic interrogation in mice, semi-high-throughput imaging in human islet spheroids and living human pancreas slices, and PET/MR imaging of innervation and inflammation in recent-onset T1D.A consistent finding in human T1D pancreata is the patchy distribution of islet inflammation; some lobes of the pancreas have large immune infiltrates and loss of beta cells whereas others remain unaffected.

This has led to hypotheses that the innervation pattern of the pancreas is involved in regulating islet inflammation. Evidence is emerging on an interplay between the nervous and immune systems in various pathophysiological scenarios.

Our data supports the notion that nerves have a regulatory effect, and modulation halts onset of disease by acting on islet-resident macrophages.I plan to use a three-pronged approach of (i) basic neuro-immune connections in the pancreas in mouse models (ii) higher-throughput readouts in a human islet spheroids and living human pancreas slices, and (iii) a clinical imaging strategy to correlate innervation and inflammation in recent-onset T1D patients.

This comprehensive approach holds promise to provide an overview of the pathophysiologic events in T1D, and mechanistic insights into how sympathetic signals may act immune-regulatory to provide targets for modulation of autoimmunity.