Effects of Extracellular Mechanics on Mechanosensory and Central Neuron Function

脑血管功能障碍几乎伴随着所有已知的紧张型疾病--一种 神经退行性疾病，导致记忆、执行功能和一般认知能力受损 拒绝。最近对创伤性脑损伤(TBI)机制的研究揭示了 与神经退行性疾病相关的病理学与那些 跟随着TBI。综上所述，这些发现表明，异常的神经机械 并强调认知能力的下降。神经血管学与脑内脑室和导水管网络 已知会随着血流和年龄的变化而波动--这两个因素都是 痴呆症。假设这些动态结构周围的中枢神经元具有多种类型 对物理环境变化做出反应的分子蛋白质传感器，尽管很少有研究 直接研究了这些受体及其在健康和疾病中的作用。为了解决这一知识差距，这项工作 本研究旨在量化细胞外机械环境对神经功能的影响。至 为了实现这一目标，候选人将首先在F-99期间作为博士生实现两个拟议的科学目标 获奖阶段，然后作为博士后学者在K-00阶段获奖。的第一个目标 这份提案介绍了候选人在赞助商的实验室里完成的论文研究。这 已完成的研究证明了目标2和目标3中提出的工作的可行性。在目标2中， 候选人将继续他们的研究，研究细胞外力学对机械感觉的影响 无脊椎动物模型线虫的神经元功能，其触摸感觉反映了大脑中的触摸感受器 人类外周神经系统。这项工作结合了最先进的相关力谱和 在三维、可调谐、粘弹性底物中进行神经元培养的荧光显微镜。对于 这一奖项的K-00阶段，如目标3所述，候选人将延长这项工作的临床相关性 通过研究脊椎动物疾病模型的体外神经力学。总的来说，候选人的研究 对博士后奖学金的兴趣是(1)确定机械应变的颅内来源，(2)解决 这些菌株如何改变中枢神经元功能，以及(3)将这些发现作为识别 中枢神经元中机械感受器的新类别。该奖项提供的培训支持将服务于 作为一个跳板，候选人将以独立神经学家的身份开始他们的职业生涯， 在工程学和神经科学的交界处识别机械转导信号通路 中枢神经元及其在神经变性中的作用。候选人的长期职业目标是建立一个 研究计划，将利用对基础神经生物学的理解来确定治疗靶点。

Cerebrovascular dysfunction accompanies nearly all of the known forms of tauopathies--a form of neurodegenerative disorders that result in impaired memory, executive function, and general cognitive decline. Recent efforts to understand the mechanisms underlying traumatic brain injury (TBI) have revealed several startling similarities between the pathologies associated with neurodegenerative diseases and those following TBI. Combined, these findings suggest a potential relationship between aberrant neural mechanical and stress cognitive decline. Neurovasculature and the network of ventricles and aqueducts within the brain are known to fluctuate in volume with changes in blood flow and age--both of which are risk factors for dementia. Central neurons surrounding these dynamic structures are hypothesized to possess multiple types of molecular protein sensors that respond to physical environmental changes, though few studies have directly studied these receptors and their role in health and disease. To address this knowledge gap, the work proposed here aims to quantify the effects of the extracellular mechanical environment on neural function. To achieve this aim, the candidate will achieve two proposed scientific aims first as a PhD student during the F-99 phase of the award, and then as a postdoctoral scholar during the K-00 phase of the award. The first aim of this proposal presents dissertation research completed to date by the candidate in the sponsor’s lab. This completed research demonstrates the feasibility of the work proposed in Aims 2 and 3. In Aim 2, the candidate will continue their research studying the effects of extracellular mechanics on mechanosensory neuron function in an invertebrate model, C. elegans, whose touch sensation mirrors touch receptors in the human peripheral nervous system. This work combines state-of-the-art, correlative force spectroscopy and fluorescence microscopy with neuronal culture in three-dimensional, tunable, viscoelastic substrates. For the K-00 phase of this award, as described in Aim 3, the candidate will extend the clinical relevance of this work by studying in vitro neural mechanics in vertebrate models of disease. Broadly, the candidate’s research interest for the postdoctoral scholarship is to (1) identify intracranial sources of mechanical strain, (2) address how these strains alter central neuron function, and (3) use these findings as a springboard for identifying novel classes of mechanoreceptors in central neurons. The training support provided by this award will serve as a springboard with which the candidate will launch their career as an independent neuroscientist, working at the interface of engineering and neuroscience to identify mechanotransduction signalling pathways in central neurons and their role in neurodegeneration. The candidate’s long-term career goal is to establish a research program that will employ an understanding of basic neurobiology to identify therapeutic targets.