Mechanics of Trauma-Induced Tauopathy

反复头部受伤的运动员和士兵会增加患慢性创伤性脑病(CTE)的风险，CTE是一种神经退行性疾病，其特征是认知功能下降和大脑中tau蛋白的复杂沉积。虽然这种相关性已经得到了很好的证实，但在损伤过程中作用于大脑的力量如何导致CTE的发生还不清楚。这个项目将专注于了解神经元的机械拉伸如何导致tau错误定位于树突棘，在那里它改变了神经元接收来自其他神经元的电化学信号的能力。此外，该项目还将研究单个神经元在损伤过程中的变形如何影响这种错误定位和功能丧失的可能性。脑损伤和CTE每年影响数以百万计的美国人，随着在以往战争中暴露于简易爆炸装置的士兵年龄的增长，CTE病例很可能会增加。这些研究将是从机制上理解CTE启动的第一步，并可能为未来更好的CTE治疗提供重要线索。认识到所有年龄段的儿童都可能因为从自行车上摔下来或从事接触性运动而受到脑损伤，研究人员开发了一个旨在向小学生传授头盔设计和头部损伤的外展项目，该项目将作为该奖项的一部分扩大。该项目有三个研究目标。第一个实验将通过实验确定拉伸导致tau错误定位的机制，包括通过快速拉伸大鼠海马神经元，聚焦于微管破裂和局灶性肿胀。第二项研究将确定细胞结构和取向相对于外加变形如何影响tau错误定位和随后树突状细胞功能的丧失。最终目标将开发一套基于神经元结构和脑组织变形动力学来预测直肠痉挛的理论模型，包括粘弹性连续介质模型、轴突模型和细胞骨架模型。该奖项反映了NSF的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。

Athletes and soldiers exposed to repeated head injuries have increased risk of developing chronic traumatic encephalopathy (CTE), a neurodegenerative disease characterized by decreased cognitive function and tangled deposits of the protein tau in the brain. Though this correlation is well established, it is not known how the forces acting on the brain during injury cause development of CTE. This project will focus on understanding how mechanical stretching of neurons induces tau to be mislocalized to dendritic spines, where it alters the ability of neurons to receive electrochemical signals from other neurons. In addition, the project will study how the deformation of individual neurons during injury influences the likelihood of this mislocalization and loss of function. Brain injury and CTE affect millions of Americans every year, and it is likely that CTE cases will increase as soldiers exposed to improvised explosive devices in previous wars age. These studies will be first steps toward a mechanistic understanding of CTE initiation, and could provide important clues for better CTE treatment in the future. Recognizing that children of all ages can get brain injuries from falling off bikes or playing contact sports, the investigators have developed an outreach program aimed at teaching elementary school children about helmet design and head injury, which will be expanded as part of this award.This project has three research aims. The first will experimentally determine the mechanism through which stretching induces tau mislocalization, including focusing on microtubule rupture and focal swelling by rapidly stretching rat hippocampal neurons. The second will determine how cell structure and orientation relative to applied deformation influences tau mislocalization and subsequent loss of dendritic function. The final aim will develop a set of theoretical models to predict tauopathy based on neuron structure and the dynamics of brain tissue deformation, including a viscoelastic continuum model, a neurite model, and a cytoskeletal model.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.