Notch-mediated dendritic regeneration for recovery after TBI

描述(申请人提供)：创伤性脑损伤(TBI)不仅导致立即的新皮质破坏(原发损伤)，而且通过原发事件触发的复杂机制继而损害存活的细胞。这种继发性损伤会导致进一步的认知、感觉和运动功能障碍。目前，还没有经过临床验证和FDA批准的药物疗法来治疗颅脑损伤患者，以减少神经损伤。脑外伤后的功能损害以前被认为是细胞迅速死亡的结果。尽管脑外伤会导致大脑皮层和海马区显著的细胞死亡，但大多数神经元在最初的损伤中幸存下来。对这些备用神经元的损伤还没有得到充分的研究，越来越多的证据表明，脑外伤后轴突受损。我们最近的研究表明，脑外伤后大量的备用神经元表现出显著的树突变性和突触消除。经历树突变性的神经元的数量比脑损伤后海马区丢失的神经元数量多数百倍。由于树突为脊柱的形成提供了巨大的表面积，并决定了突触输入的范围和范围，脑外伤后的树突变性可能导致神经元之间突触传递的显著中断，进而导致神经功能障碍。因此，颅脑损伤所致的神经功能障碍可能是损伤诱导的神经元死亡以及存活神经元的轴突损伤和树突萎缩的结果。虽然广泛的研究集中在预防脑外伤急性期的神经元死亡，但在很大程度上忽略了备用神经元的树突损伤。我们的长期目标是寻找新的方法来加强树突再生，以促进脑外伤后的功能恢复。最近，我们发现Notch信号调节哺乳动物雷帕霉素靶标(MTOR)通路的活性，并在促进出生后脑内神经元的树突树枝形成中发挥新的作用。我们推测，mTOR通路的激活增强了出生后脑神经元中树突的树枝形成，并加速了脑损伤后的功能恢复。为了提供支持这一新假说的证据，我们将使用创新的策略，包括条件转基因技术和病毒介导的单细胞基因敲除，结合著名的组织学研究来确定1)介导Notch信号增强出生后神经元树突树枝形成的分子途径(S)；以及2)评估mTOR途径的激活是否促进脑损伤后备用神经元树突的重新生长。这一建议的结果不仅将促进对出生后脑中树突可塑性的了解，而且将为促进树突再生以加速脑外伤后功能恢复的创新策略提供参考。

DESCRIPTION (provided by applicant): Traumatic Brain Injury (TBI) not only results in immediate neocortex disruption (primary injury), but also damages the surviving cells secondarily by complex mechanisms triggered by the primary event. This secondary injury leads to further cognitive, sensory, and motor dysfunction. At present, there are no clinically proven and FDA approved drug therapies for treatment of TBI patients aimed at reducing the neurological injuries. The functional impairments following TBI were previously thought to result from rapid cell death. Although TBI causes significant cell death in the cortex and hippocampus, most neurons survive the initial insult. The injuries to those spared neurons are not fully studied Mounting evidence shows axonal damage after TBI. Our recent study revealed that a significant number of spared neurons exhibit dramatic dendritic degeneration and synaptic elimination following TBI. The number of neurons that experience dendrite degeneration is hundreds of times greater than the number of neurons lost in the hippocampus following TBI. Since dendrites provide enormous surface area for spine formation and determine the range and scope of synaptic inputs, dendritic degeneration following TBI could cause significant disruption in synaptic transmission between neurons, in turn, contributing to neurological disorders. Thus, neurological disorders due to TBI could be a result of injury-induced neuronal death as well as axonal damage and dendritic atrophy of surviving neurons. While extensive studies have been focused on preventing neuronal death at the acute phase of TBI, the dendritic damage in spared neurons has been largely neglected. Our long-term goal is to identify novel approaches to enhance dendrite regeneration for functional recovery following TBI. Recently, we found that Notch signaling regulates the activity of the mammalian target of rapamycin (mTOR) pathway and plays novel roles in enhancing dendrite arborization of neurons in the postnatal brain. We hypothesize that activation of mTOR pathway enhances dendrite arborization in the neurons of the postnatal brain and accelerates functional recovery following TBI. To provide the evidence to support this novel hypothesis, we will use innovative strategies including conditional transgenic technology and viral-mediated gene knockout in single cells combined with prestigious histological studies to determine 1) the molecular pathway(s) that mediate Notch signaling-enhanced dendrite arborization of postnatally born neurons; and 2) Assess whether activation of mTOR pathway enhances dendrite re-growth in the spared neurons following TBI. The results from this proposal will not only advance the understanding of dendrite plasticity in the postnatal brain, but will also shed light on innovative strategies to promote dendrite regeneration to accelerate functional recovery following TBI.