Unlocking the neurovascular interface of peripheral nerves in homeostasis, disease and repair

The extensive network of peripheral nerves develops concurrently and in close contact with the vascular system. This spatial and functional relationship persists into adulthood, forming a neurovascular (NV) interface that shields the vulnerable neural tissue through a blood-nerve barrier (BNB), akin to the blood-brain barrier (BBB). Despite its pivotal role in peripheral nervous system (PNS) health, our understanding of the BNB is limited, impacting the design of therapies for PNS disorders linked to vascular dysfunction. Our interdisciplinary proposal aims to define the molecular, cellular, and biomechanical features of the neurovascular interface of peripheral nerves. We hypothesize that vascular cells within this neurovascular interface are crucial for maintaining BNB homeostasis and for promoting the unique regenerative capacity of the PNS after injury. To accomplish our objectives, we have adopted a cross-disciplinary, innovative and synergistic approach. We will map the nerve vascular niche using advanced transcriptomic and proteomic approaches. Taking an original angle, we will explore the impact of mechanobiology on BNB homeostasis and the vascular response to damage by designing screening assays and mouse models to discover mechanotransduction systems operating in the nerve endothelium. Using agnostic in vivo peptide phage display technology, we will map unique ""ZIP codes"" on the nerve vasculature, enabling selective targeting of the PNS. BNB homing peptides will serve as selective discovery tools to unravel the biology of the barrier and will be amenable for further refinement in preclinical setting. Finally, we will examine BNB responses to perturbations like traumatic injuries or neuropathies and develop tools to specifically target the BNB.Our project will transform the current understanding of the NV interface of the PNS, laying the foundation for targeted therapies to address BNB dysfunction and enhance clinical care for peripheral nerve disorders.""