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Axon Plasticity and Recovery of Function after Traumatic Brain Injury

脑外伤后轴突可塑性和功能恢复

基本信息

批准号：
7837637
负责人：
Neil Harris
金额：
$ 33.35万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-06-01 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7837637
关键词：
Acute Affect Aftercare American Animals Attenuated Axon Behavioral Brain Brain-Derived Neurotrophic Factor Chondroitin ABC Lyase Chondroitin Sulfate Proteoglycan Chondroitinases Chronic Cicatrix Combined Modality Therapy Contusions Data Environment Felis catus Functional Imaging Functional disorder Growth Human Pathology Hyaluronidase Image Immunohistochemistry In Situ Hybridization Infusion procedures Injury Intervention Label Lesion Life Limb structure Medical Modeling Motor Myelin Neuraxis Neuronal Plasticity Neurons Outcome Population Production Proteins Recovery Recovery of Function Reporting Research Research Personnel Reverse Transcriptase Polymerase Chain Reaction Sensory Simulate Spinal cord injury Stimulus Stroke Time Traumatic Brain Injury Walking Western Blotting attenuation axon growth axonal sprouting base behavior test cell growth controlled cortical impact critical developmental period critical period dark rearing density disability extracellular functional outcomes functional restoration improved injured neurobehavioral neuropathology novel prevent programs protein expression response

项目摘要

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) results in significant acute neurobehavioral deficits that, despite some spontaneous recovery persist at more chronic times. At least 5.3 million Americans - 2% of the U.S. population currently lives with disabilities resulting from TBI. However, beyond acute interventions there are currently no generally accepted medical treatments for reducing secondary neuropathology and promoting functional recovery after TBI. The central hypotheses of the proposed research are that: (1) limited functional recovery after TBI is due, at least in part, to inadequate axonal sprouting, (2) limited sprouting is a result of an increase in growth-inhibitory molecules (growth-IMs), (3) treatment to reduce growth-IMs will improve functional outcome, and (4) combined treatments to reduce growth-IMS and to activate cellular growth will further enhance sprouting and functional outcome. We base this hypothesis on observations after controlled-cortical impact (CCI) injury, a clinically relevent model of TBI that: 1) a persistent behavioral deficit occurs, despite functional imaging data showing activation in novel ipsi-lesional regions, 2) spontaneous axon sprouting occurs only in regions of reduced growth-inhibitory chondroitin sulphate proteoglycans (CSPGs), 3) pharmacological reduction of CSPGs increases perilesional sprouting and 4) the same treatment-induced sprouting is the anatomical substrate for enhanced functional outcome after spinal cord injury which also prolongs the critical period for plasticity in dark-reared cats. Based on these observations the focus of this proposal is on the growth-inhibitory activity of the CSPGs and their contribution to failed axon plasticity after TBI. The specific aims are to: (i) Determine the relationship between CSPG expression and spontaneous axon sprouting after CCI injury. We will examine whether spontaneous axon sprouting occurs only in regions where CSPG expression is low and where perineuronal net organization of CSPGs is reduced, (ii) Determine whether attenuating CSPG protein expression enhances subsequent axonal sprouting. We will use chondroitinase ABC to reduce ipsi-lesional CSPG proteins to enhance and sustain axonal sprouting, (iii) Determine whether axon sprouting is regionally and temporally specific to novel regions of fore-limb evoked functional activation after injury. We will assess whether axonal sprouting provides the anatomical substrate for functional recovery in the same animal, (iv) Determine if attenuating CSPG expression improves functional and neurobehavioural outcome. We will use functional microPET imaging and behavioral tests of fore-limb function to determine if enhancing sprouting improves outcome, (v) Determine if activating cellular growth status by BDNF infusion combined with attenuation of CSPG expression results in further increases in sprouting and improved behavioral outcome.

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Traumatic brain injury reveals novel cell lineage relationships within the subventricular zone.

DOI：
10.1016/j.scr.2014.04.013
发表时间：
2014-07
期刊：
STEM CELL RESEARCH
影响因子：
1.2
作者：
Thomsen, Gretchen M.;Le Belle, Janel E.;Harnisch, Jessica A.;Mc Donald, Whitney S.;Hovda, David A.;Sofroniew, Michael V.;Kornblum, Harley I.;Harris, Neil G.
通讯作者：
Harris, Neil G.

Chondroitinase enhances cortical map plasticity and increases functionally active sprouting axons after brain injury.