Effects of Extracellular Mechanics on Mechanosensory and Central Neuron Function

脑血管功能障碍几乎伴随所有已知形式的牛头病

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.