Notch-mediated dendritic regeneration for recovery after TBI

描述（由申请人提供）：创伤性脑损伤（TBI）不仅会导致立即的新皮层破坏（原发性损伤），还会通过原发性事件触发的复杂机制继发性损害存活细胞。这种继发性损伤导致进一步的认知、感觉和运动功能障碍。目前，还没有临床证明和FDA批准的用于治疗TBI患者的旨在减少神经损伤的药物疗法。TBI后的功能障碍以前被认为是由快速细胞死亡引起的。虽然TBI导致皮质和海马中的显著细胞死亡，但大多数神经元在最初的损伤中存活。对这些幸存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，TBI后轴突损伤。我们最近的研究表明，大量的备用神经元表现出显着的树突状变性和突触消除后TBI。经历树突变性的神经元的数量是TBI后海马中失去的神经元数量的数百倍。由于树突为棘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，因此TBI后的树突变性可能导致神经元之间突触传递的显著中断，进而导致神经系统疾病。因此，TBI引起的神经系统疾病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。虽然广泛的研究已经集中在防止神经元死亡在急性期的TBI，在备用神经元的树突状细胞损伤已在很大程度上被忽视。我们的长期目标是确定新的方法，以加强树突再生功能恢复后TBI。最近，我们发现Notch信号调节哺乳动物雷帕霉素靶蛋白（mTOR）通路的活性，并在促进出生后大脑神经元树突分支中发挥新的作用。我们假设mTOR通路的激活增强了出生后脑神经元中的树突分支，并加速了TBI后的功能恢复。为了提供支持这一新假说的证据，我们将采用创新的策略，包括条件性转基因技术和病毒介导的单细胞基因敲除，并结合著名的组织学研究，以确定1）介导Notch信号增强出生后神经元树突树枝化的分子途径;和2）评估mTOR途径的激活是否增强TBI后备用神经元中的树突再生长。该提案的结果不仅将促进对出生后大脑中树突可塑性的理解，而且还将揭示促进树突再生以加速TBI后功能恢复的创新策略。 公共卫生相关性：创伤性脑损伤（TBI）是儿童和年轻人死亡的主要原因。许多患者留下了严重的认知障碍、运动障碍和癫痫。目前，对这些TBI相关疾病没有有效的治疗方法。该提案旨在确定TBI后的神经可塑性，并测试创新策略，以鼓励神经再生，加速TBI后的功能恢复。

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. PUBLIC HEALTH RELEVANCE: Traumatic brain injury (TBI) is the leading cause of death in children and young adults. Many patients are left with substantial cognitive impairment, movement disorders, and epilepsy. At present, there is no effective treatment for these TBI-associated disorders. This proposal is designed to determine neural plasticity following TBI and test innovative strategies to encourage neural regeneration for accelerating functional recovery following TBI.