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Genetic and Physical Basis of Mechanical Neuroprotection

机械神经保护的遗传和物理基础

基本信息

批准号：
9005894
负责人：
Miriam B Goodman
金额：
$ 36.69万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-03-01 至 2020-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9005894
关键词：
Actins Acute Affect Afferent Neurons Anemia Animal Model Animals Axon Behavior Biochemical Biochemistry Biological Assay Blood capillaries Brain Diseases Caenorhabditis elegans Cell membrane Cells Collaborations Confocal Microscopy Cytoskeleton Defect Dendritic Spines Development Disease Dissection Erythrocytes Esthesia Fluorescence Resonance Energy Transfer Future Gene Transfer Techniques Genes Genetic Head Health Human Image In Vitro Injury Investigation Ion Channel Joints Knowledge Label Life Link Location Mammals Measures Mechanical Stress Mechanics Mechanoreceptors Modeling Molecular Morphology Motor Neurons Movement Muscle Mutation Nervous System Physiology Nervous system structure Neurites Neurons Neurosciences Organism Pain Physiology Predisposition Process Proprioception Protein Isoforms Proteins Research Risk Factors Role Sensory Signal Transduction Skin Spectrin Speed Stress Stretching Susceptibility Gene Testing Touch sensation Transcript Transgenic Animals Transgenic Organisms Translating Traumatic Brain Injury Work alpha Spectrin base beta Spectrin betaIV spectrin capillary cell type design digital imaging dimer experience flexibility image processing in vivo insight migration mutant neglect neuroprotection novel potential biomarker receptor relating to nervous system resilience response sensor somatosensory tool trafficking

项目摘要

DESCRIPTION (provided by applicant): The development and function of the nervous system is regulated not only by electrical and biochemical signals, but also by mechanical inputs. For instance, most if not all neurons generate mechanical stress and experience strain during migration, axon outgrowth, and dendritic spine remodeling. With a few notable exceptions, however, the study of cell mechanics has been neglected in neuroscience. We seek to fill this knowledge gap by investigating the genetic and physical basis of how neurons withstand mechanical stress focusing on C. elegans touch receptor neurons as a model. Key entry points for this investigation are the findings that loss of unc-70 ß spectrin function makes C. elegans neurons vulnerable to damage induced by normal movement and the well-known function for actin-spectrin networks in protecting red blood cells from the mechanical strains generated as they transit through tiny capillaries. In new work, we establish a simple visible assay for loss of spectrin function in the ventral touch receptor neurons and create transgenic animals expressing a genetically-encoded strain sensor that enables us to visualize how body bending and touch sensation affects stress in neural actin-spectrin networks. The proposed research combines genetic dissection, high-speed quantitative confocal microscopy, and in vitro biochemistry to investigate the role of spectrin networks in mechanical neuroprotection and sensory mechanoelectrical transduction. This work has the potential to transform understanding of neuronal cell mechanics and the contribution of actin-spectrin networks in this process. The new knowledge we seek to acquire could provide insight into the genetic basis of mechanical neuroprotection and potential risk factors related to traumatic brain injury.

描述（由申请人提供）：神经系统的发育和功能不仅受电信号和生化信号的调节，还受机械输入的调节。例如，大多数（如果不是全部的话）神经元在迁移、轴突生长和树突棘重塑期间产生机械应力并经历应变。然而，除了少数明显的例外，细胞力学的研究在神经科学中一直被忽视。我们试图通过研究神经元如何承受机械应力的遗传和物理基础来填补这一知识空白，重点是C。elegans触摸受体神经元作为模型。这项研究的关键切入点是发现unc-70 β血影蛋白功能的丧失使C.线虫神经元容易受到正常运动引起的损伤，肌动蛋白-血影蛋白网络具有众所周知的功能，可以保护红细胞免受通过微小毛细血管时产生的机械应力的影响。在新的工作中，我们建立了一个简单的可见测定损失的 Spectrin在腹侧触觉受体神经元中发挥作用，并创造出表达遗传编码的应变传感器的转基因动物，使我们能够可视化身体弯曲和触觉如何影响神经肌动蛋白-Spectrin网络中的压力。拟议的研究结合了遗传解剖，高速定量共聚焦显微镜和体外生物化学，以研究血影蛋白网络在机械神经保护和感觉机械电转导中的作用。这项工作有可能改变对神经细胞力学的理解，以及肌动蛋白-血影蛋白网络在这一过程中的贡献。我们寻求获得的新知识可以深入了解机械神经保护的遗传基础和与创伤性脑损伤相关的潜在风险因素。