Effects of Extracellular Mechanics on Mechanosensory and Central Neuron Function

脑血管功能障碍伴随着几乎所有已知形式的tau蛋白病--一种形式的脑血管疾病。 导致记忆、执行功能和一般认知功能受损的神经退行性疾病 下降最近对创伤性脑损伤（TBI）机制的研究表明， 与神经退行性疾病相关的病理学和那些 TBI之后。结合起来，这些发现表明异常神经机械之间的潜在关系， 和压力认知能力下降。脑内的神经血管和脑室及导水管网络 众所周知，随着血流和年龄的变化， 痴呆围绕这些动态结构的中枢神经元被假设具有多种类型 分子蛋白质传感器对物理环境变化做出反应，尽管很少有研究 直接研究这些受体及其在健康和疾病中的作用。为了弥补这一知识差距， 本文提出的目的是量化细胞外机械环境对神经功能的影响。到 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 在K-00阶段的奖励，然后作为博士后学者。的首要目标 该计划介绍了候选人在赞助商实验室完成的论文研究。这 已完成的研究表明，目标2和目标3所建议的工作是可行的。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 神经元功能的无脊椎动物模型，C。它的触觉反映了大脑中的触觉感受器， 人类周围神经系统这项工作结合了最先进的相关力谱和 荧光显微镜与神经元培养在三维，可调，粘弹性基板。为 该奖项的K-00阶段，如目标3所述，候选人将扩展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 博士后奖学金的兴趣是（1）确定颅内机械应变源，（2）解决 这些菌株如何改变中枢神经元功能，以及（3）将这些发现用作识别 中枢神经元中的新型机械感受器。该奖项提供的培训支持将有助于 作为一个跳板，候选人将开始他们的职业生涯作为一个独立的神经科学家，工作 在工程和神经科学的接口，以确定机械转导信号通路， 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 该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.