Alpha II-Spectrin: Mechanical Spring and Structural Scaffold for the Nucleoskeleton

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The research objective of this award is to determine how opposing mechanical elements of the nucleus help maintain proper shape of the organelle which houses the DNA. The nucleus of mammalian cells has a peripheral network of lamin filaments that provides stiffness. Preliminary results show that alpha II-spectrin provides mechanical resilience or recoil, which may be described as a "spring". Studies conducted under this award will test the mechanisms of this spring hypothesis by quantifying recovery of nuclei in cells under force. The force responsiveness of the lamin network and subnuclear components including the DNA will be observed during mechanical testing in cells that have been depleted of alpha II-spectrin. Also, binding partners will be determined for alpha II-spectrin using purified proteins and protein fragments so that a more accurate description of the architecture can be identified. Although strength and stiffness is important at every level of physiology, mechanical recoil and resilience also plays an important role in maintaining proper homeostasis. Here, the discovery and investigation of alpha II-spectrin as a nuclear mechanical spring will allow a thorough understanding of integrated cellular mechanics and mechanobiology. If successful, these studies will advance the understanding of nuclear structure, gene expression and mechanical responsiveness of cells. Also, results may provide insights into the large number of human diseases and progressive dystrophies associated with lamins and other nuclear structural proteins. The education plan focuses on enhancing ethics training for undergraduate researchers. To directly impact students from underrepresented groups nationally and internationally, advanced online learning initiatives in Anatomy and Physiology are being developed as a supplement for community college education in pre-medicine.