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

该奖项的研究目标是确定细胞核的相对机械元素如何帮助维持容纳DNA的细胞器的正确形状。哺乳动物细胞的细胞核具有提供硬度的核纤层蛋白丝的外围网络。初步结果表明，α II-血影蛋白提供机械弹性或反冲，这可以被描述为“弹簧”。在该奖项下进行的研究将通过量化细胞核在力下的恢复来测试这个弹簧假说的机制。在已耗尽α II-血影蛋白的细胞中进行机械试验期间，将观察到核纤层蛋白网络和亚核组分（包括DNA）的力响应性。此外，将使用纯化的蛋白质和蛋白质片段确定α II-血影蛋白的结合伴侣，以便可以鉴定结构的更准确描述。虽然强度和刚度在生理学的各个层面都很重要，但机械反冲和弹性在维持适当的稳态方面也起着重要作用。在这里，发现和调查的α II-血影蛋白作为一个核机械弹簧将允许一个完整的细胞力学和机械生物学的理解。如果成功，这些研究将促进对细胞核结构，基因表达和机械反应的理解。此外，研究结果可能会提供与核纤层蛋白和其他核结构蛋白相关的大量人类疾病和进行性营养不良的见解。教育计划的重点是加强对本科研究人员的道德培训。为了直接影响国内和国际上代表性不足的群体的学生，正在开发解剖学和生理学的高级在线学习计划，作为医学预科社区学院教育的补充。

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.