Neurons, the basic cells of nerves, are one of the most difficult to regenerate after disease or injury. If advances are going to be made in engineering systems that support nerve regrowth and regeneration, it is imperative that we develop a full understanding of how these cells respond to their biomechanical environment. This study will investigate how changes in the extracellular mechanical environment affects the development of neurons and the branching of dendrite -- the structure that receives signals from other nerve cells. Knowledge gained from this project will help to develop strategies that may eventually improve treatments for degenerative neural diseases or following nerve injury due to trauma. The research team will integrate students at all levels, from graduate school through high school, as well as teachers into the project. In addition, outreach will involve the development of hands-on projects and demonstrations that can introduce the public to concepts of neuroscience, imaging, and biomechanics.
Two hypotheses are being investigated related to neuron growth and development within this project. The first is that local structural changes associated with applied cell forces act to transduce extracellular mechanical cues to the cytoskeleton. The second is that local changes in cellular tension in response to changes in the extracellular mechanical microenvironment act to transduce extracellular mechanical cues to the cytoskeleton. The research team will make use of a vinculin force sensor for which the tension can be measured using Forster resonance energy transfer (FRET). This mechanical measurement will be combined with fluorescence imaging of the cytoskeletal dynamics. Thus, the specific aims of this project are to: 1) demonstrate that vinculin expression changes as a function of substrate stiffness and tension; 2) demonstrate that vinculin tension is altered in response to changes in substrate stiffness and investigate the role of integrin, cadherin, and neurotransmitter receptors in mediating this response; and 3) investigate the relationship between vinculin tension, microtubule assembly, and the resulting dendritic branching.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
