Defining Cardiac Innervation and Reinnervation During Cardiac Injury
Abstract
Cardiac nerves regulate many important physiological functions of the heart such as heart rate and contractility. The emerging role of cardiac nerves as regulators of tissue maintenance and regeneration is beginning to be appreciated. It has been reported that neonatal mice are capable of regenerating their hearts following injury within a brief period after birth. Furthermore, it has been demonstrated that nerves in the heart play an important role in promoting neonatal mouse heart regeneration. However, the adult human heart is incapable of regeneration following injury. In addition, cardiac nerves can undergo repair and rewiring following heart injury, where pathological reinnervation may result in deadly arrhythmias and sudden cardiac death. This is in contrast to the neonatal mouse regenerative response, where normal reinnervation takes place and no arrhythmias or heart rate changes are detected. Interestingly, heart transplant recipients have a completely denervated heart, but recent evidence suggests that the hosts’ hearts slowly become reinnervated within the first year. This suggests that reinnervation patterns following adult injury and during neonatal heart regeneration vary widely, and proper innervation patterning is important for survival and normal cardiac function following injury. Thus, understanding reinnervation patterns and the cellular components involved in this process following adult cardiac injury represents a unique approach to identify novel therapies to stimulate adult heart repair. Currently, limited information is available regarding heart innervation patterns and nerve cell expansion under pathological conditions. Our current knowledge on cardiac innervation is based on histological approaches, which does not faithfully reflect the innervation patterns in vivo under physiological and pathological conditions. Thus, our goal in this proposal is to apply novel approaches using genetic lineage-tracing and clonal analysis, together with tissue clarity techniques and 3D imaging to define cardiac innervation patterns under physiological conditions and following injury. Our proposed experiments will define the molecular signature of physiological and pathological innervation following cardiac injury. This proposal has important scientific and therapeutic potential, as it will reveal the unique role of cardiac nerves in health and disease. Furthermore, our innovative approach will more broadly serve as a roadmap towards studying how the nervous system communicates with various tissues during development, as well as in the context of regeneration and disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210094
Entities
People
- Ahmed I Mahmoud
Organizations
- United States Army
- University of Wisconsin–Madison