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Molecular Mechanisms and Treatment of Diffuse Axonal Injury

弥漫性轴突损伤的分子机制和治疗

基本信息

批准号：
10023949
负责人：
Brian J. Kelley
金额：
$ 15.02万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-30 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10023949
关键词：
Address Advisory Committees Affect Algorithms Antibodies Axon Axotomy Biomechanics Calpain Childhood Clinical Collaborations Communities Cytoskeletal Proteins Cytoskeleton Deformity Development Diffuse Diffuse Axonal Injury Diffuse Brain Injury Doctor of Philosophy Ensure Environment Event Experimental Models Fellowship Future Genomics Histologic Histology Injury Knock-out Knockout Mice Lead Mediating Mentors Methods Microtubules Mind Molecular Molecular Structure Morbidity - disease rate Myelin Nature Nervous System Trauma Neurobiology Neuronal Plasticity Neurons Nodal Outcome Pathogenesis Pathologic Pathologic Processes Pathology Patients Pennsylvania Peptide Hydrolases Physicians Population Positioning Attribute Program Development Protein Biochemistry Protein Subunits Public Health Ranvier&apos s Nodes Recovery Rehabilitation therapy Research Research Personnel Research Proposals Residencies Resources Role Scientist Secondary to Severities Shapes Site Spectrin Spinal Structural Protein Techniques Testing Therapeutic Training Programs Trauma Traumatic Brain Injury Universities axon injury base behavioral outcome behavioral study calpastatin career demographics design effective therapy effectiveness evaluation fluid percussion injury improved improved outcome insight instructor mouse model neurofilament neuroimaging neuroinflammation neuron loss neuronal cell body neurosurgery novel overexpression predictive modeling preservation prevent professor response success theories therapy design treatment strategy

项目摘要

Project Summary This new investigator proposal describes a five-year training program for the development of a physician- scientist career studying traumatic brain injury (TBI). This investigator completed a Ph.D. in neurobiology focused on mechanisms and neuroinflammatory responses to diffuse axonal injury (DAI). This investigator completed neurosurgery residency, two fellowships in pediatric neurosurgery and pediatric spinal deformity, and is currently a Clinical Instructor at the University of Pennsylvania. In carrying out the proposed research, the principle investigator will acquire expertise in protein biochemistry, knockout genomics, behavioral studies, and advanced neuroimaging techniques. Dr. Douglas Smith, Professor and Chair of Research in the Department of Neurosurgery, will mentor the principle investigator's scientific development. An advisory committee of outstanding, nationally recognized scientists will provide scientific and career advice. The Department of Neurosurgery at the University of Pennsylvania is committed to providing an ideal setting and resources to ensure the principle investigator's success. The research proposal and environment will allow the principle investigator to develop an academic career and become a leader in the neurotrauma community. Research will focus on the selective vulnerability of unmyelinated axon segments to initiating mechanisms of diffuse TBI as well as treatment strategies to overcome DAI pathobiology. DAI pathogenesis proceeds through a cascade of events leading to delayed or secondary axotomy. This creates a therapeutic window during which treatments may mitigate or prevent axon disconnection. Mechanisms of DAI cytoskeletal injury remain poorly understood and there are no treatments. The proposal seeks to determine precise DAI initiating loci, explain the cytoskeletal protein spectrin's role in axonal injury, and investigate two neuroprotective paradigms to mitigate DAI pathobiology. Using an experimental diffuse TBI murine model, the Specific Aims include: 1.) Determine if the axon initial segment and/or nodes of Ranvier are sites of secondary axotomy following diffuse TBI and 2.) Determine spectrin-mediated contributions to secondary axotomy following diffuse TBI. This proposal will be the first to test the hypothesis that disruption of the spectrin cytosketeton at excitable domains along the axon serves as a nidus for injury. Neuroprotective paradigms include preservation of the spectrin cytoskeleton through exogenous and endogenous inhibition of the protease calpain, which targets spectrin for degradation. The proposed research will improve our understanding of DAI-mediated cytoskeletal injury and test neuroprotective strategies designed to prevent secondary axotomy. The integration of histology, behavioral outcomes, and advanced neuroimaging techniques will create a model that predicts injury severity and prognosticates recovery after diffuse brain injury.

项目总结