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Mechanisms of remodeling circuit connectivity after traumatic brain injury

脑外伤后重塑回路连接的机制

基本信息

批准号：
8869961
负责人：
DAVID F MEANEY
金额：
$ 40万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8869961
关键词：
Algorithms Brain Brain Diseases CREB1 gene Calcineurin Calcium Cause of Death Cessation of life Characteristics Cognitive deficits Data Dimensions Disease Equilibrium Genetic Transcription Goals Health Human Image In Vitro Individual Injury Lead Link Maintenance Measures Mechanics Mediating Mitochondria Modeling N-Methyl-D-Aspartate Receptors Nerve Degeneration Neurons Outcome Pathway interactions Patients Pattern Pharmacy (field)Phenotype Phosphorylation Population Pre-Clinical Model Protocols documentation Public Health Receptor Signaling Recovery Relative (related person)Role Signal Pathway Signal Transduction Structure Testing Therapeutic Time Trauma Traumatic Brain Injury Work calmodulin-dependent protein kinase II cognitive recovery disability improved in vivo injured innovation insight mitochondrial permeability transition pore nervous system disorder neural circuit novel pre-clinical reconstruction relating to nervous system repaired response

项目摘要

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) remains a major public health problem and is on pace to become the third leading cause of death and disability in the world population by 2020. Although we know that both neuronal degeneration and cognitive deficits are common features of human TBI, we are only beginning to appreciate an entirely new dimension of the disease: how brain networks change immediately after injury, and how cognitive recovery may depend critically on rebuilding these networks. The broad, long-term goal of our work identifies the fundamental mechanisms on how neural activity and intracellular signaling pathways together contribute to rebuilding a circuit after TBI. To our knowledge, our preliminary data is the first evidence showing how the structure of neural circuits changes after TBI, and the first observation on how combining circuit activation with pharmaceutics can together rebuild a network. We build on our preliminary data and propose the following aims: Specific Aim 1: To examine mechanisms of neuronal disconnection from a network after mechanical injury in vitro and in vivo. Specific Aim 2: To determine mechanisms for the activity-induced re-integration of neurons into an injured microcircuit over time. Our general hypotheses are: (a) Connectivity directly influences neuronal disconnection from a network following injury, as well as network recovery (b) neuronal re-integration into the network is mediated by calcineurin activity and CREB-phosphorylation, (c) neuronal disconnection is mediated by mitochondrial signaling, and (d) prolonged circuit activation, in combination with pharmaceutics, can optimally control the reconstruction of networks. Impact: Knowing the mechanisms for remodeling neuronal connections in a circuit over time after TBI will give us insight into treatments protecting the network structure. Once the mechanisms for remodeling circuitry after TBI are better understood, we envision testing therapies in preclinical TBI models within the next 5-10 years. Broadly, we believe this work will shift the therapeutic focus away from reducing neuronal death and towards approaches to rebuild functional circuits after TBI.

描述（由申请人提供）：创伤性脑损伤（TBI）仍然是一个主要的公共卫生问题，到2020年将成为世界人口死亡和残疾的第三大原因。虽然我们知道神经元变性和认知缺陷是人类TBI的共同特征，但我们才刚刚开始认识到这种疾病的一个全新层面：大脑网络在受伤后如何立即改变，以及认知恢复如何关键地依赖于重建这些网络。我们工作的广泛，长期目标是确定神经活动和细胞内信号通路如何共同促进TBI后重建电路的基本机制。据我们所知，我们的初步数据是显示TBI后神经回路结构如何变化的第一个证据，也是第一次观察到回路激活与药物如何共同重建网络。我们建立在我们的初步数据，并提出以下目标：具体目标1：研究机制的神经元断开后，在体外和体内的机械损伤的网络。具体目标2：确定活动诱导的神经元随时间重新整合到受损微电路中的机制。我们的一般假设是：（a）连接性直接影响损伤后神经元从网络断开以及网络恢复（B）神经元重新整合到网络中由钙调磷酸酶活性和CREB-磷酸化介导，（c）神经元断开由线粒体信号传导介导，和（d）延长的回路激活，与药物组合，可以最佳地控制网络的重建。影响力：了解TBI后随着时间的推移重塑回路中神经元连接的机制将使我们深入了解保护网络结构的治疗方法。一旦更好地理解了TBI后重塑电路的机制，我们设想在未来5-10年内在临床前TBI模型中测试疗法。总的来说，我们相信这项工作将把治疗重点从减少神经元死亡转移到TBI后重建功能回路的方法上。