Mechanics of Trauma-Induced Tauopathy

创伤引起的 Tau 蛋白病的机制

基本信息

批准号：
1935834
负责人：
Patrick Alford
金额：
$ 43.32万
依托单位：
University of Minnesota-Twin Cities
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-15 至 2024-06-30
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1935834&HistoricalAwards=false
关键词：
Mechanics Trauma Induced Tauopathy

项目摘要

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.

经常遭受头部损伤的运动员和士兵患慢性创伤性脑病 (CTE) 的风险会增加，这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 蛋白沉积物缠结。尽管这种相关性已得到充分证实，但尚不清楚损伤期间作用在大脑上的力如何导致 CTE 的发生。该项目将重点了解神经元的机械拉伸如何诱导 tau 蛋白错误定位到树突棘，从而改变神经元接收来自其他神经元的电化学信号的能力。此外，该项目还将研究损伤期间单个神经元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 每年影响数百万美国人，而且随着以前战争中暴露于简易爆炸装置的士兵年龄的增长，CTE 病例可能会增加。这些研究将是理解 CTE 发生机制的第一步，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从自行车上摔下来或参加接触性运动而受到脑损伤，研究人员制定了一项外展计划，旨在向小学生传授头盔设计和头部损伤的知识，该计划将作为该奖项的一部分进行扩展。项目有三个研究目标。第一个项目将通过实验确定拉伸引起 tau 蛋白错位的机制，包括通过快速拉伸大鼠海马神经元来关注微管破裂和局灶性肿胀。第二个将确定细胞结构和相对于施加变形的方向如何影响 tau 错位和随后的树突功能丧失。最终目标是开发一套基于神经元结构和脑组织变形动力学来预测tau蛋白病的理论模型，包括粘弹性连续体模型、神经突模型和细胞骨架模型。该奖项反映了NSF的法定使命，并被视为值得通过使用基金会的智力优点和更广泛的影响审查标准进行评估来支持。