CAREER: Engineering nervous tissue in vitro: Discovering the mechanisms of rapid axon stretch growth.

New Jersey Institute Of Technology, Newark NJ

Investigators

Abstract

Pfister 0747615 The research objective of this proposal is to define and analyze how stretching forces, associated with the growth of an organism, initiate unique neurobiological mechanisms to accommodate stretch growth of axons, driving the natural and rapid formation of long nerves and white matter tracts. In a developing embryo, axons navigate via a growth cone over seeming large distances to reach their targets. However, well after axons integrate with their targets and establish synaptic connections, animals and their nervous systems continue to grow several orders of magnitude. It is conceivable that stretching forces, exerted on axons by the enlarging body, serves as the mechanism that initiates and maintains stretch growth of the axon cylinder. An in vitro tissue engineering method has been developed to recapitulate this fundamentally different and rapid form of axonal growth that occurs during an organism's development. Far exceeding the rate of growth cone extension, this new-found form of nervous system growth, extreme axon stretch growth, can reach at least 10mm per day. These investigations mapped out the biomechanical boundaries that allow integrated axon bundles to quickly adapt to escalating stretch-growth rates, producing large axon fascicles 10cm in length and potentially much longer. Remarkably, these extreme stretch growth conditions also stimulate expansion of axon caliber, while maintaining a normal cytoskeletal ultrastructure and the ability to convey action potentials. Surprisingly, few studies have examined the effects of mechanical stretch on the rapid growth potential of axons. Axon stretch growth presents a novel opportunity to greatly expand upon the current understanding of nervous system growth with real potential to discover new targets to accelerate regeneration, offering an unexplored direction in nerve repair. Additional scientific benefits of this model could be the ability to engineer structured nervous tissue to study the pathology of nervous system diseases or the neurophysiological behavior of an organized network of neurons. Students at all levels will be included in this exciting and challenging opportunity to explore new territory in bioengineering and neuroscience. Opportunities and mentoring will also be provided for students with disabilities as well as encouragement and assistance for high school students with disabilities and their college plans.