Network Synergies in Tissue Homeostasis and Stromal Prevention of Inflammatory Disease.

Introduction

Inflammation has evolved to protect us from the outside world. However, in doing so, it consumes large amounts of energy and causes collateral damage, thus requiring strict control on multiple levels. While the mechanisms that govern inflammation once ongoing are well defined, we lack basic knowledge of the processes that regulate its actual onset in vivo.

Importance of Understanding Inflammation

Only by understanding the mechanisms that orchestrate tissue stress responses and defend against unwanted inflammation will we pave the way for new therapeutic approaches in future precision medicine. This includes not only treating inflammation once it is active but also preventing inflammatory disease from developing in the first place.

Hypothesis

I hypothesize that prevention of inflammation can be accomplished at the level of tissue homeostasis and cooperative stromal biology. The stroma that underlies any given tissue is not a passive scaffold. Instead, it comprises a functional network that regulates key aspects of tissue physiology as an adaptive and self-organizing system ("homeostat").

Role of Resident Tissue Macrophages

Resident tissue macrophages (RTM) - the tissue’s very own regulators of inflammation - are physically connected to this homeostat and thereby directly integrated into its cooperative signaling grid. Hard-wired communication mechanisms and synergies allow RTM-stroma networks to operate as a functional syncytium, a hitherto unknown operating system that coordinates stress responses and actively prevents the onset of inflammation.

Proposed Approach

Here, I propose a pioneering tissue biology approach to decipher the stromal homeostat. By combining unique bioimaging with computational 3D reconstruction and multidimensional profiling, I will quantitatively unravel complex cell interactions to explain the mechanisms and implications of stromal network communication in a living tissue.

Objectives

Thereby, I aim to:

1. Elucidate homeostat-operating principles.
2. Establish top-down control of inflammatory tissue checkpoints.
3. Apply these findings to clinically relevant inflammatory diseases.